Noninvasive measurement of chemical substances

ABSTRACT

Utilization of a contact device placed on the eye in order to detect physical and chemical parameters of the body as well as the non-invasive delivery of compounds according to these physical and chemical parameters, with signals being transmitted continuously as electromagnetic waves, radio waves, infrared and the like. One of the parameters to be detected includes non-invasive blood analysis utilizing chemical changes and chemical products that are found in the conjunctiva and in the tear film. A transensor mounted in the contact device laying on the cornea or the surface of the eye is capable of evaluating and measuring physical and chemical parameters in the eye including non-invasive blood analysis. The system utilizes eye lid motion and/or closure of the eye lid to activate a microminiature radio frequency sensitive transensor mounted in the contact device. The signal can be communicated by wires or radio telemetered to an externally placed receiver. The signal can then be processed, analyzed and stored. Several parameters can be detected including a complete non-invasive analysis of blood components, measurement of systemic and ocular blood flow, measurement of heart rate and respiratory rate, tracking operations, detection of ovulation, detection of radiation and drug effects, diagnosis of ocular and systemic disorders and the like.

[0001] This application is a continuing application of application Ser.No. 09/517,124, filed Feb. 29, 2000, which is a continuing applicationof application Ser. No. 09/184,127, filed Nov. 2, 1998, now U.S. Pat.No. 6,120,460, which is a continuing application of application Ser. No.08/707,508, filed Sep. 4, 1996, now U.S. Pat. No. 5,830,139, all ofwhich are incorporated herein in their entirety by reference.

FIELD OF THE INVENTION

[0002] The present invention includes a contact device for mounting on apart of the body to measure bodily functions and to treat abnormalconditions indicated by the measurements.

BACKGROUND OF THE INVENTION

[0003] The present invention relates to a tonometer system for measuringintraocular pressure by accurately providing a predetermined amount ofapplanation to the cornea and detecting the amount of force required toachieve the predetermined amount of applanation. The system is alsocapable of measuring intraocular pressure by indenting the cornea usinga predetermined force applied using an indenting element and detectingthe distance the indenting element moves into the cornea when thepredetermined force is applied, the distance being inverselyproportional to intraocular pressure. The present invention also relatesto a method of using the tonometer system to measure hydrodynamiccharacteristics of the eye, especially outflow facility.

[0004] The tonometer system of the present invention may also be used tomeasure hemodynamics of the eye, especially ocular blood flow andpressure in the eye's blood vessels. Additionally, the tonometer systemof the present invention may be used to increase and measure the eyepressure and evaluate, at the same time, the ocular effects of theincreased pressure.

[0005] Glaucoma is a leading cause of blindness worldwide and, althoughit is more common in adults over age 35, it can occur at any age.Glaucoma primarily arises when intraocular pressure increases to valueswhich the eye cannot withstand.

[0006] The fluid responsible for pressure in the eye is the aqueoushumor. It is a transparent fluid produced by the eye in the ciliary bodyand collected and drained by a series of channels (trabecular meshwork,Schlemm's canal and venous system). The basic disorder in most glaucomapatients is caused by an obstruction or interference that restricts theflow of aqueous humor out of the eye. Such an obstruction orinterference prevents the aqueous humor from leaving the eye at a normalrate. This pathologic condition occurs long before there is a consequentrise in intraocular pressure. This increased resistance to outflow ofaqueous humor is the major cause of increased intraocular pressure inglaucoma-stricken patients.

[0007] Increased pressure within the eye causes progressive damage tothe optic nerve. As optic nerve damage occurs, characteristic defects inthe visual field develop, which can lead to blindness if the diseaseremains undetected and untreated. Because of the insidious nature ofglaucoma and the gradual and painless loss of vision associatedtherewith, glaucoma does not produce symptoms that would motivate anindividual to seek help until relatively late in its course whenirreversible damage has already occurred. As a result, millions ofglaucoma victims are unaware that they have the disease and faceeventual blindness. Glaucoma can be detected and evaluated by measuringthe eye's fluid pressure using a tonometer and/or by measuring the eyefluid outflow facility. Currently, the most frequently used way ofmeasuring facility of outflow is by doing indentation tonography.According to this technique, the capacity for flow is determined byplacing a tonometer upon the eye. The weight of the instrument forcesaqueous humor through the filtration system, and the rate at which thepressure in the eye declines with time is related to the ease with whichthe fluid leaves the eye.

[0008] Individuals at risk for glaucoma and individuals who will developglaucoma generally have a decreased outflow facility. Thus, themeasurement of the outflow facility provides information which can helpto identify individuals who may develop glaucoma, and consequently willallow early evaluation and institution of therapy before any significantdamage occurs.

[0009] The measurement of outflow facility is helpful in makingtherapeutic decisions and in evaluating changes that may occur withtime, aging, surgery, or the use of medications to alter intraocularpressure. The determination of outflow facility is also an importantresearch tool for the investigation of matters such as drug effects, themechanism of action of various treatment modalities, assessment of theadequacy of antiglaucoma therapy, detection of wide diurnal swings inpressure and to study the pathophysiology of glaucoma.

[0010] There are several methods and devices available for measuringintraocular pressure, outflow facility, and/or various otherglaucoma-related characteristics of the eye. The following patentsdisclose various examples of such conventional devices and methods:PATENT NO. PATENTEE 5,375,595 Sinha et al. 5,295,495 Maddess 5,251,627Morris 5,217,015 Kaye et al. 5,183,044 Nishio et al. 5,179,953 Kursar5,148,807 Hsu 5,109,852 Kaye et al. 5,165,409 Coan 5,076,274 Matsumoto5,005,577 Frenkel 4,951,671 Coan 4,947,849 Takahashi et al. 4,944,303Katsuragi 4,922,913 Waters, Jr. et al. 4,860,755 Erath 4,771,792 Seale4,628,938 Lee 4,305,399 Beale 3,724,263 Rose et al. 3,585,849 Grolman3,545,260 Lichtenstein et al.

[0011] Still other examples of conventional devices and/or methods aredisclosed in Morey, Contact Lens Tonometer, RCA Technical Notes, No.602, December 1964; Russell & Bergrnanson, Multiple Applications of theNCT: An Assessment of the Instrument's Effect on IOP, Ophthal. Physiol.Opt., Vol. 9, April 1989, pp. 212-214; Moses & Grodzki, ThePneumatonograph: A Laboratory Study, Arch. Ophthalmol., Vol.97, March1979, pp.547-552; and C. C. Collins, Miniature Passive PressureTransensor for Implanting in the Eye, IEEE Transactions on Bio-medicalEngineering, April 1967, pp. 74-83.

[0012] In general, eye pressure is measured by depressing or flatteningthe surface of the eye, and then estimating the amount of forcenecessary to produce the given flattening or depression: Conventionaltonometry techniques using the principle of applanation may provideaccurate measurements of intraocular pressure, but are subject to manyerrors in the way they are currently being performed. In addition, thepresent devices either require professional assistance for their use orare too complicated, expensive or inaccurate for individuals to use athome. As a result, individuals must visit an eye care professional inorder to check their eye pressure. The frequent self-checking ofintraocular pressure is useful not only for monitoring therapy andself-checking for patients with glaucoma, but also for the earlydetection of rises in pressure in individuals without glaucoma and forwhom the elevated pressure was not detected during their office visit.

[0013] Pathogens that cause severe eye infection and visual impairmentsuch as herpes and adenovirus as well as the virus that causes AIDS canbe found on the surface of the eye and in the tear film. Thesemicroorganisms can be transmitted from one patient to another throughthe tonometer tip or probe. Probe covers have been designed in order toprevent transmission of diseases but are not widely used because theyare not practical and provide less accurate measurements. Tonometerswhich prevent the transmission of diseases, such as the “air-puff” typeof tonometer also have been designed, but they are expensive and provideless accurate measurements. Any conventional direct contact tonometerscan potentially transmit a variety of systemic and ocular diseases.

[0014] The two main techniques for the measurement of intraocularpressure require a force that flattens or a force that indents the eye,called “applanation” and “indentation” tonometry respectively.

[0015] Applanation tonometry is based on the Imbert-Fick principle. Thisprinciple states that for an ideal dry, thin walled sphere, the pressureinside the sphere equals the force necessary to flatten its surfacedivided by the area of flattening. P=F/A (where. P=pressure, F=force,A=area). In applanation tonometry, the cornea is flattened, and bymeasuring the applanating force and knowing the area flattened, theintraocular pressure is determined.

[0016] By contrast, according to indentation tonometry (Schiotz), aknown weight (or force) is applied against the cornea and theintraocular pressure is estimated by measuring the linear displacementwhich results during deformation or indentation of the cornea. Thelinear displacement caused by the force (is indicative of intraocularpressure. In particular, for standard forces and standard dimensions ofthe indenting device, there are known tables which correlate the lineardisplacement and intraocular pressure.

[0017] Conventional measurement techniques using applanation andindentation are subject to many errors. The most frequently usedtechnique in the clinical setting is contact applanation using Goldmantonometers. The main sources of errors associated with this methodinclude the addition of extraneous pressure on the cornea by theexaminer, squeezing of the eyelids or excessive widening of the lidfissure by the patient due to the discomfort caused by the tonometerprobe resting upon the eye, and inadequate or excessive amount of dye(fluorescein). In addition, the conventional techniques depend uponoperator skill and require that the operator subjectively determinealignment, angle and amount of depression. Thus, variability andinconsistency associated with less valid measurements are problemsencountered using the conventional methods and devices.

[0018] Another conventional technique involves air-puff tonometerswherein a puff of compressed air of a known volume and pressure isapplied against the surface of the eye, while sensors detect the timenecessary to achieve a predetermined amount of deformation in the eye'ssurface caused by application of the air puff. Such a device isdescribed, for example, in U.S. Pat. No. 3,545,260 to Lichtenstein etal. Although the non-contact (air-puff) tonometer does not use dye anddoes not present problems such as extraneous pressure on the eye by theexaminer or the transmission of diseases, there are other problemsassociated therewith. Such devices, for example, are expensive, requirea supply of compressed gas, are considered cumbersome to operate, aredifficult to maintain in proper alignment and depend on the skill andtechnique of the operator. In addition, the individual tested generallycomplains of pain associated with the air discharged toward the eye, anddue to that discomfort many individuals are hesitant to undergo furthermeasurement with this type of device. The primary advantage of thenon-contact tonometer is its ability to measure pressure withouttransmitting diseases, but they are not accepted in general as providingaccurate measurements and are primarily useful for large-scale glaucomascreening programs.

[0019] Tonometers which use gases, such as the pneumotonometer, haveseveral disadvantages and limitations. Such device are also subject tothe operator errors as with Goldman's tonometry. In addition, thisdevice uses freon gas, which is not considered environmentally safe.Another problem with this device is that the gas is flammable and aswith any other aerosol-type can, the can may explode if it gets too hot.The gas may also leak and is susceptible to changes in cold weather,thereby producing less accurate measurements. Transmission of diseasesis also a problem with this type of device if probe covers are notutilized.

[0020] In conventional indentation tonometry (Schiotz), the main sourceof errors are related to the application of a relatively heavy tonometer(total weight at least 16.5 g) to the eye and the differences in thedistensibility of the coats of the eye. Experience has shown that aheavy weight causes discomfort and raises the intraocular pressure.Moreover the test depends upon a cumbersome technique in which theexaminer needs to gently place the tonometer onto the cornea withoutpressing the tonometer against the globe. The accuracy of conventionalindentation may also be reduced by inadequate cleaning of the instrumentas will be described later. The danger of transmitting infectiousdiseases, as with any contact tonometer, is also present withconventional indentation.

[0021] A variety of methods using a contact lens have been devised,however, such systems suffer from a number of restrictions and virtuallynone of these devices is being widely utilized or is accepted in theclinical setting due to their limitations and inaccurate readings.Moreover, such devices typically include instrumented contact lensesand/or cumbersome and complex contact lenses.

[0022] Several instruments in the prior art employ a contact lens placedin contact with the sclera (the white part of the eye). Such systemssuffer from many disadvantages and drawbacks. The possibility ofinfection and inflammation is increased due to the presence of a foreignbody in direct contact with a vascularized part of the eye. As aconsequence, an inflammatory reaction around the device may occur,possibly impacting the accuracy of any measurement. In addition, thelevel of discomfort is high due to a long period of contact with ahighly sensitive area of the eye. Furthermore, the device could slideand therefore lose proper alignment, and again, preventing accuratemeasurements to be taken. Moreover, the sclera is a thick and almostnon-distensible coat of the eye which may further impair the ability toacquire accurate readings. Most of these devices utilize expensivesensors and complicated electric circuitry imbedded in the lens whichare expensive, difficult to manufacture and sometimes cumbersome.

[0023] Other methods for sensing pressure using a contact lens on thecornea have been described. Some of the methods in this prior art alsoemploy expensive and complicated electronic circuitry and/or transducersimbedded in the contact lens. In addition, some devices usepiezoelectric material in the lens and the metalization of components ofthe lens overlying the optical axis decreases the visual acuity ofpatients using that type of device. Moreover, accuracy is decreasedsince the piezoelectric material is affected by small changes intemperature and the velocity with which the force is applied. There arealso contact lens tonometers which utilize fluid in a chamber to causethe deformation of the cornea; however, such devices lack means foralignment and are less accurate, since the flexible elastic material isunstable and may bulge forward. In addition, the fluid therein has atendency to accumulate in the lower portion of the chamber, thus failingto produce a stable flat surface which is necessary for an accuratemeasurement.

[0024] Another embodiment uses a coil wound about the inner surface ofthe contact lens and a magnet subjected to an externally createdmagnetic field. A membrane with a conductive coating is compressedagainst a contact completing a short circuit. The magnetic field forcesthe magnet against the eye and the force necessary to separate themagnet from the contact is considered proportional to the pressure. Thisdevice suffers from many limitations and drawbacks. For example, thereis a lack of accuracy since the magnet will indent the cornea and whenthe magnet is pushed against the eye, the sclera and the coats of theeye distort easily to accommodate the displaced intraocular contents.This occurs because this method does not account for the ocularrigidity, which is related to the fact that the sclera of one person'seye is more easily stretched than the sclera of another. An eye with alow ocular rigidity will be measured and read as having a lowerintraocular pressure than the actual eye's pressure. Conversely, an eyewith a high ocular rigidity distends less easily than the average eye,resulting in a reading which is higher than the actual intraocularpressure. In addition, this design utilizes current in the lens which,in turn, is in direct contact with the body. Such contact isundesirable. Unnecessary cost and complexity of the design with circuitsimbedded in the lens and a lack of an alignment system are also majordrawbacks with this design.

[0025] Another disclosed contact lens arrangement utilizes a resonantcircuit formed from a single coil and a single capacitor and a magnetwhich is movable relative to the resonant circuit. A further design fromthe same disclosure involves a transducer comprised of a pressuresensitive transistor and complex circuits in the lens which constitutethe operating circuit for the transistor. All three of the disclosedembodiments are considered impractical and even unsafe for placement ona person's eye. Moreover, these contact lens tonometers areunnecessarily expensive, complex, cumbersome to use and may potentiallydamage the eye. In addition none of these devices permits measurement ofthe applanated area, and thus are generally not very practical.

[0026] The prior art also fails to provide a sufficiently accuratetechnique or apparatus for measuring outflow facility. Conventionaltechniques and devices for measuring outflow facility are limited inpractice and are more likely to produce erroneous results because bothare subject to operator, patient and instrument errors.

[0027] With regard to operator errors, the conventional test for outflowfacility requires a long period of time during which there can be notilting of the tonometer. The operator therefore must position and keepthe weight on the cornea without moving the weight and without pressingthe globe.

[0028] With regard to patient errors, if during the test the patientblinks, squeezes, moves, holds his breath, or does not maintainfixation, the test results will not be accurate. Since conventionaltonography takes about four minutes to complete and generally requiresplacement of a relatively heavy tonometer against the eye, the chancesof patients becoming anxious and therefore re acting to the mechanicalweight placed on their eyes is increased.

[0029] With regard to instrument errors, after each use, the tonometerplunger and foot plate should be rinsed with water followed by alcoholand then wiped dry with lint-free material. If any foreign material dryswithin the foot plate, it can detrimentally affect movement of theplunger and can produce an incorrect reading.

[0030] The conventional techniques therefore are very difficult toperform and demand trained and specialized personnel. Thepneumotonograph, besides having the problems associated with thepneumotonometer itself, was considered “totally unsuited to tonography.”(Report by the Committee on Standardization of Tonometers of theAmerican Academy of Ophthalmology; Archives Ophthalmol., 97:547-552,1979). Another type of tonometer (Non Contact “Air Puff” Tonometer—U.S.Pat. No. 3,545,260) was also considered unsuitable for tonography.(Ophthalmic & Physiological Optics, 9(2):212-214, 1989). Presently thereare no truly acceptable means for self-measurement of intraocularpressure and outflow facility.

[0031] In relation to an additional embodiment of the present invention,blood is responsible not only for the transport of oxygen, food,vitamins, water, enzymes, white and red blood cells, and geneticmarkers, but also provides an enormous amount of information in regardsto the overall health status of an individual. The prior art related toanalysis of blood relies primarily on invasive methods such as with theuse of needles to draw blood for further analysis and processing. Veryfew and extremely limited methods for non-invasive evaluating bloodcomponents are available.

[0032] In the prior art for example, oxygenated hemoglobin has beenmeasured non-invasively. The so called pulse oximeter is based ontraditional near infrared absorption spectroscopy and indirectlymeasures arterial blood oxygen with sensors placed over the skinutilizing LEDs emitting at two wave lengths around 940 and 660nanometers. As the blood oxygenation changes, the ratio of the lighttransmitted by the two frequencies changes indicating the amount ofoxygenated hemoglobin in the arterial blood of the finger tip. Thepresent systems are not accurate and provide only the amount ofoxygenated hemoglobin in the finger tip.

[0033] The skin is a thick layer of tissue with a thick epithelium. Theepithelium is the superficial layers of tissue and vary according to theorgan or location in the body. The skin is thick because it is in directcontact with the environment and it is the barrier between the internalorgans and the external environment. The skin is exposed and subject toall kind of noxious external agents on a daily basis. Stratifiedsquamous keratinizing epithelium layers of the skin have a strong,virtually impermeable layer called the stratum corneum and keratin. Thekeratin that covers the skin is a thick layer of a hard and dead tissuewhich creates another strong barrier of protection against pathogenicorganisms but also creates a barrier to the proper evaluation of bodilyfunctions such as non-invasive blood analysis and cell analysis.

[0034] Another drawback in using the skin is due to the fact that thesuperficial layer of tissue covering the skin does not allow acquisitionof important information, only present in living tissue. In addition,the other main drawback in using the skin is because the blood vesselsare not easily accessible. The main vascular supply to the skin islocated deep and distant from the superficial and still keratinizedimpermeable skin layer.

[0035] Prior art attempts to use the skin and other areas of the body toperform non-invasive blood analysis, diagnostics and evaluations ofbodily functions such as oral, nasal and ear mucosa. These areas havebeen found to be unsuitable for such tasks. Moreover, placement of anobject in oral or nasal mucosa can put the user at risk of aspirationand obstructing the airway which is a fatal event.

[0036] Another drawback in using the skin is the presence of variousappendages and glands which prevent adequate measurements from beingacquired such as hair, sweat glands, and sebaceous glands withcontinuous outflowing of sebum. Moreover, the layers of the skin vary inthickness in a random fashion. Furthermore, the layers of the skin arestrongly attached to each other, making the surgical implantation of anydevice extremely difficult. Furthermore the skin is a highly innervatedarea which is highly sensitive to painful stimuli.

[0037] In order to surgically implant a device under the skin there isneed for invasive application of anesthetic by injection around the areato be incised and the obvious risk of infection. Moreover, the structureof the skin creates electrical resistance and makes acquisition ofelectrical signals a much more difficult procedure.

[0038] Attempts to use electroosmosis as a flux enhancement byiontophoresis with increased passage of fluid through the skin withapplication of electrical energy, do not provide accurate or consistentsignals and measurements due to the skin characteristics describedabove. Furthermore there is a significant delay in the signalacquisition when electroosmosis-based systems are used on the skinbecause of the anatomy and physiology of the skin which is thick and haslow permeability.

[0039] Previously, a watch with sensing elements in apposition to theskin has been used in order to acquire a signal to measure glucose.Because of the unsuitable characteristics of the skin the watch has toactually shock the patient in order to move fluid. The fluid measuredprovides inconsistent, inaccurate and delayed results because of theunsuitable characteristics of the skin as described above. It is easy tosee how unstable the watch is if one were to observe how much their ownwatch moves up and down and around one=s pulse during normal use. Thereis no natural stable nor consistent correct apposition of the sensorsurface to the tissue, in this case the dead keratin layer of the thickskin.

[0040] Previously invasive means were used with tearing of the skin inthe tip of the fingers to acquire whole blood, instead of plasma, forglucose measurement. Besides being invasive, whole blood from thefingers is used which has to be corrected for plasma levels. Plasmalevels provide the most accurate evaluation of blood glucose.

[0041] The conventional way for blood analysis includes intense laborand many expenses using many steps including cumbersome, expensive andbulky laboratory equipment. A qualified medical professional is requiredto remove blood and this labor is certainly costly. The professionalsexpose themselves to the risk of acquiring infections and fatal diseasessuch as ADS, hepatitis, and other viral and prion diseases. In order toprevent that possible contamination a variety of expensive measures andtools are taken, but still only providing partial protection to themedical professional and the patient. A variety of materials are usedsuch as alcohol swabs, syringes, needles, sterile vials, gloves as wellas time and effort. Moreover, effort, time and money must be spent withthe disposal of biohazard materials such as the disposal of the sharpsand related biohazard material used to remove blood. These practicesnegatively affect the environment as those biohazard materials arenon-degradable and obviously made of non-recycled material.

[0042] In addition, these practices comprise a painful procedure withpuncturing the skin and putting the patient and nurse at risk forinfection, fatal diseases, contamination, and blood borne diseases.After all of this cumbersome, costly, time-consuming and hazardousprocedure, the vials with blood have to be transported by a humanattendant to the laboratory which is also costly. At the laboratory theblood is placed in other machines by a trained human operator with allof the risks and costs associated with the procedure of dealing withblood.

[0043] The conventional laboratory instruments then have to separate theblood using special and expensive machines and then materials are sentfor further processing and analysis by a trained human operator.Subsequent to that the result is printed and sent to the patient and/ordoctor, most frequently by regular mail. All of this process inlaboratories is risky, complex, cumbersome, and expensive; and this isonly for one test.

[0044] If a patient is admitted to a hospital, this very laborious andexpensive process could happen several times a day. Only one simpleblood test result can be over $100 dollars and this cost is easilyexplained by the labor and materials associated with the cost related tomanipulation of blood and protection against infections as describedabove. If four tests are needed over 24 hours, as may occur withadmitted patients, the cost then can increase to $400 dollars.

[0045] The world and in particular the United States face challenginghealth care costs with a grim picture of rapidly rising health careexpenditures with a rapid increase in the number and frequency oftesting. Today, the worldwide diabetic population alone is over 125million and is expected to reach 250 million by the year 2008. TheUnited States spent over $140 billion dollars on diabetes alone in 1998.More frequent control of blood glucose is known to prevent complicationsand would substantially reduce the costs of the disease.

[0046] According to the projections by the Health Care FinancingAdministration of the United States Department of Health and HumanServices, health care spending as a share of U.S. gross domestic product(GDP) is estimated to increase from 13 percent to potentially andamazingly close to 20% of the United States GDP in the near future,reaching over $2 trillion dollars a year, which clearly demonstrates howunwise health care spending can affect the overall economy of a nation.

[0047] The World Health Organization reported in 1995, the percentage oftotal spending on health by various governments clearly indicatinghealth care costs as a serious global problem and important factorconcerning the overall utilization of public money. Public spending onhealth by the United States government was 47%, while United Kingdom was84%, France was 81%, Japan was 78%, Canada was 71%, Italy was 70% andMexico was 56%.

[0048] Infrared spectroscopy is a technique based on the absorption ofinfrared radiation by substances with the identification of saidsubstances according to its unique molecular oscillatory patterndepicted as specific resonance absorption peaks in the infrared regionof the electromagnetic spectrum. Each chemical substance absorbsinfrared radiation in a unique manner and has its own unique absorptionspectra depending on its atomic and molecular arrangement andvibrational and rotational oscillatory pattern. This unique absorptionspectra allows each chemical substance to basically have its owninfrared spectrum, also referred as fingerprint or signature which canbe used to identify each of such substances.

[0049] Radiation containing various infrared wavelengths is emitted atthe substance or constituent to be measured, referred to herein as“substance of interest”, in order to identify and quantify saidsubstance according to its absorption spectra. The amount of absorptionof radiation is dependent upon the concentration of said chemicalsubstance being measured according to Beer-Lambert's Law.

[0050] When electromagnetic energy is emitted an enormous amount ofinterfering constituents, besides the substance of interest, are alsoirradiated such as skin, fat, wall of blood vessels, bone, cartilage,water, blood, hemoglobin, albumin, total protein, melanin, and variousother interfering substances. Those interfering constituents andbackground noise such as changes in pressure and temperature of thesample irradiated drastically reduce the accuracy and precision of themeasurements when using infrared spectroscopy. Those many constituentsand variables including the substance of interest form then anabsorption spectrum for each wavelength. The sum of the absorption foreach wavelength of radiation by all of the constituents and variablesgenerates the total absorption with said total absorption spectrum beingmeasured at two or more wavelengths of emission.

[0051] In order then to achieve the concentration of the substance ofinterest, a procedure must be performed to subtract the statisticalabsorption spectra for each of the various intervening tissues andinterfering constituents, with the exception of the substance ofinterest being measured. It is then assumed that all of the interferingconstituents were accounted for and completely eliminated and that theremainder is the real spectra of the substance of interest. It has beenvery difficult to prove this assumption in vivo as no devices or methodsin the prior art have yet shown to be clinically useful.

[0052] In the prior art the interfering constituents and variablesintroduce significant source of errors which are particularly criticalsince the background noise as found in the prior art tremendouslyexceeds the signal of the substance of interest which is found inminimal concentrations relative to the whole sample irradiated.Furthermore, in the prior art, the absorption of a solute such asglucose is very small compared to the other various interferingconstituents which leads to many statistical errors preventing theaccurate statistical measurement of glucose concentration. A variety ofother techniques using infrared devices and methods have been describedbut all of them suffer from the same limitation due to the great amountof interference and noise.

[0053] Other techniques based on comparison with a known referencesignal as with phase sensitive techniques have also the same limitationsand drawbacks due to the great number of interfering constituents andgeneration of only a very weak signal. The interfering constituents aresource of many artifacts, errors, and variability which leads toinadequate signal and severe reduction of the signal to noise ratio.Besides, calculation errors are common because of the many interferingsubstances and because the spectra of interfering constituents canoverlap with the spectra of the substance of the interest beingmeasured. If adequate signal to noise can be achieved, infraredspectroscopy should be able to provide a clinically useful device anddetermine the concentration of the substance of interest precisely andaccurately.

[0054] Attempts in the prior art using infrared spectroscopy fornoninvasive measurement of chemical substances have failed to accuratelyand precisely measure chemical substances such as for example glucose.The prior art have used transcutaneous optical means, primarily usingthe skin non-invasively, to determine the concentration of chemicalsubstances. The prior art has also used invasive means with implant ofsensors inside blood vessels or around the blood vessels. The prior artused polarized light directed at the aqueous humor of the eye, which islocated inside the eye, in an attempt to measure glucose in said aqueoushumor. However, precise measurements are very difficult to achieveparticularly when there is substantial background noise and minimalconcentration of the substance of interest as it occurs in the aqueoushumor of the eye. Besides, polarized light techniques as used in theaqueous humor of the eye can only generate a very weak signal and thereis low concentration of the solute in the aqueous sample. Thecombination of those factors and presence of interfering constituentsand variables prevent accurate measurements to be achieved when usingthe aqueous humor of the eye.

[0055] The most frequent optical approaches in the prior art were basedon measuring chemical substances using the skin. Other techniquesinclude measuring substances in whole blood in the blood vessel (eithernon-invasively transcutaneously or invasively around or inside the bloodvessel). Yet attempts were made to measure substances present ininterstitial fluid with devices implanted under the skin. Attempts werealso made by the prior art using the oral mucosa and tongue.

[0056] Mucosal surfaces such as the oral mucosa are made to stand longwear and tear as occurs during mastication. If the oral mucosa or tonguelining were thin with exposed vessels, one would easily bleed duringchewing. Thus, those areas have rather thick lining and without plasmaleakage. Furthermore these mucosal areas have no natural means forapposition of a sensor such as a natural pocket formation.

[0057] Since there is still a low signal with an enormous amount ofinterfering constituents, useful devices using the oral mucosal, tongue,and other mucosa such as genito-urinary and gastrointestinal have notbeen developed. The prior art also attempted to measure glucose usingfar infrared thermal emission from the body, but a clinically usefuldevice has not been developed due to the presence of interferingelements and great thermal instability of the sample. Near infraredspectroscopy and far-infrared techniques have been tried by the priorart as means to non-invasively measure glucose, but accuracy andprecision for clinical application has not been achieved.

[0058] Therefore remains a need to provide a method and apparatuscapable of delivering a higher signal to noise by reducing oreliminating interfering constituents, noise, and other variables, whichwill ultimately provide the accuracy and precision needed for usefulclinical application.

SUMMARY OF THE INVENTION

[0059] In contrast to the various prior art devices, the apparatus ofthe present invention offers an entirely new approach for themeasurement of intraocular pressure and eye hydrodynamics. The apparatusoffers a simple, accurate, low-cost and safe means of detecting andmeasuring the earliest of abnormal changes taking place in glaucoma, andprovides a method for the diagnosis of early forms of glaucoma beforeany irreversible damage occurs. The apparatus of this invention providesa fast, safe, virtually automatic, direct-reading, comfortable andaccurate measurement utilizing an easy-to-use, gentle, dependable andlow-cost device, which is suitable for home use.

[0060] Besides providing a novel method for a single measurement andself-measurement of intraocular pressure, the apparatus of the inventioncan also be used to measure outflow facility and ocular rigidity. Inorder to determine ocular rigidity it is necessary to measureintraocular pressure under two different conditions, either withdifferent weights on the tonometer or with the indentation tonometer andan applanation tonometer. Moreover, the device can perform applanationtonography which is unaffected by ocular rigidity because the amount ofdeformation of the cornea is so very small that very little is displacedwith very little change in pressure. Large variations in ocularrigidity, therefore, have little effect on applanation measurements.

[0061] According to the present invention, a system is provided formeasuring intraocular pressure by applanation. The system includes acontact device for placement in contact with the cornea and an actuationapparatus for actuating the contact device so that a portion thereofprojects inwardly against the cornea to provide a predetermined amountof applanation. The contact device is easily sterilized for multipleuse, or alternatively, can be made inexpensively so as to render thecontact device disposable. The present invention, therefore, avoids thedanger present in many conventional devices of transmitting a variety ofsystemic and ocular diseases.

[0062] The system further includes a detecting arrangement for detectingwhen the predetermined amount of applanation of the cornea has beenachieved and a calculation unit responsive to the detecting arrangementfor determining intraocular pressure based on the amount of force thecontact device must apply against the cornea in order to achieve thepredetermined amount of applanation.

[0063] The contact device preferably includes a substantially rigidannular member, a flexible membrane and a movable central piece. Thesubstantially rigid annular member includes an inner concave surfaceshaped to match an outer surface of the cornea and having a hole definedtherein. The subsannular member preferably has a maximum thickness atthe hole and a progressively decreasing thickness toward a periphery ofthe substantially rigid annular member.

[0064] The flexible membrane is preferably secured to the inner concavesurface of the substantially rigid annular member. The flexible membraneis coextensive with at least the hole in the annular member and includesat least one transparent area. Preferably, the transparent area spansthe entire flexible membrane, and the flexible membrane is coextensivewith the entire inner concave surface of the rigid annular member.

[0065] The movable central piece is slidably disposed within the holeand includes a substantially flat inner side secured to the flexiblemembrane. A substantially cylindrical wall is defined circumferentiallyaround the hole by virtue of the increased thickness of the rigidannular member at the periphery of the hole. The movable central pieceis preferably slidably disposed against this wall in a piston-likemanner and has a thickness which matches the height of the cylindricalwall. In use, the substantially flat inner side flattens a portion ofthe cornea upon actuation of the movable central piece by the actuationapparatus.

[0066] Preferably, the actuation apparatus actuates the movable centralpiece to cause sliding of the movable central piece in the piston-likemanner toward the cornea. In doing so, the movable central piece and acentral portion of the flexible membrane are caused to project inwardlyagainst the cornea. A portion of the cornea is thereby flattened.Actuation continues until a predetermined amount of applanation isachieved.

[0067] Preferably, the movable central piece includes a magneticallyresponsive element arranged so as to slide along with the movablecentral piece in response to a magnetic field, and the actuationapparatus includes a mechanism for applying a magnetic field thereto.The mechanism for applying the magnetic field preferably includes a coiland circuitry for producing an electrical current through the coil in aprogressively increasing manner. By progressively increasing thecurrent, the magnetic field is progressively increased. The magneticrepulsion between the actuation apparatus and the movable central piecetherefore increases progressively, and this, in turn, causes aprogressively greater force to be applied against the cornea until thepredetermined amount of applanation is achieved.

[0068] Using known principles of physics, it is understood that theelectrical current passing through the coil will be proportional to theamount of force applied by the movable central piece against the corneavia the flexible membrane. Since the amount of force required to achievethe predetermined amount of applanation is proportional to intraocularpressure, the amount of current required to achieve the predeterminedamount of applanation will also be proportional to the intraocularpressure.

[0069] The calculation unit therefore preferably includes a memory forstoring a current value indicative of the amount of current passingthrough the coil when the predetermined amount of applanation isachieved and also includes a conversion unit for converting the currentvalue into an indication of intraocular pressure.

[0070] The magnetically responsive element is circumferentiallysurrounded by a transparent peripheral portion. The transparentperipheral portion is aligned with the transparent area and permitslight to pass through the contact device to the cornea and also permitslight to reflect from the cornea back out of the contact device throughthe transparent peripheral portion.

[0071] The magnetically responsive element preferably comprises anannular magnet having a central sight hole through which a patient isable to see while the contact device is located on the patient's cornea.The central sight hole is aligned with the transparent area of theflexible membrane.

[0072] A display is preferably provided for numerically displaying theintraocular pressure detected by the system. Alternatively, the displaycan be arranged so as to give indications of whether the intraocularpressure is within certain ranges.

[0073] Preferably, since different patients may have differentsensitivities or reactions to the same intraocular pressure, the rangesare calibrated for each patient by an attending physician. This way,patients who are more susceptible to consequences from increasedintraocular pressure may be alerted to seek medical attention at apressure less than the pressure at which other less-susceptible patientsare alerted to take the same action.

[0074] The detecting arrangement preferably comprises an opticalapplanation detection system. In addition, a sighting arrangement ispreferably provided for indicating when the actuation apparatus and thedetecting arrangement are properly aligned with the contact device.Preferably, the sighting arrangement includes the central sight hole inthe movable central piece through which a patient is able to see whilethe device is located on the patient's cornea. The central sight hole isaligned with the transparent area, and the patient preferably achieves agenerally proper alignment by directing his vision through the centralsight hole toward a target mark in the actuation apparatus.

[0075] The system also preferably includes an optical distance measuringmechanism for indicating whether the contact device is spaced at aproper axial distance from the actuation apparatus and the detectingarrangement. The optical distance measurement mechanism is preferablyused in conjunction with the sighting arrangement and preferablyprovides a visual indication of what corrective action should be takenwhenever an improper distance is detected.

[0076] The system also preferably includes an optical alignmentmechanism for indicating whether the contact device is properly alignedwith the actuation apparatus and the detecting arrangement. The opticalalignment mechanism preferably provides a visual indication of whatcorrective action should be taken whenever a misalignment is detected,and is preferably used in conjunction with the sighting arrangement, sothat the optical alignment mechanism merely provides indications ofminor alignment corrections while the sighting arrangement provides anindication of major alignment corrections.

[0077] In order to compensate for deviations in corneal thickness, thesystem of the present invention may also include an arrangement formultiplying the detected intraocular pressure by a coefficient (or gain)which is equal to one for corneas of normal thickness, less than one forunusually thick corneas, and a gain greater than one for unusually thincorneas.

[0078] Similar compensations can be made for corneal curvature, eyesize, ocular rigidity, and the like. For levels of corneal curvaturewhich are higher than normal, the coefficient would be less than one.The same coefficient would be greater than one for levels of cornealcurvature which are flatter than normal.

[0079] In the case of eye size compensation, larger than normal eyeswould require a coefficient which is less than one, while smaller thannormal eyes require a coefficient which is greater than one.

[0080] For patients with “stiffer” than normal ocular rigidities, thecoefficient is less than one, but for patients with softer ocularrigidities, the coefficient is greater than one.

[0081] The coefficient (or gain) may be manually selected for eachpatient, or alternatively, the gain may be selected automatically byconnecting the apparatus of the present invention to a known pachymetryapparatus when compensating for corneal thickness, a known keratometerwhen compensating for corneal curvature, and/or a known biometer whencompensating for eye size.

[0082] The contact device and associated system of the present inventionmay also be used to detect intraocular pressure by indentation. Whenindentation techniques are used in measuring intraocular pressure, apredetermined force is applied against the cornea using an indentationdevice. Because of the force, the indentation device travels in towardthe cornea, indenting the cornea as it travels. The distance traveled bythe indentation device into the cornea in response to the predeterminedforce is known to be inversely proportional to intraocular pressure.Accordingly, there are various known tables which, for certain standardsizes of indentation devices and standard forces, correlate the distancetraveled and intraocular pressure.

[0083] Preferably, the movable central piece of the contact device alsofunctions as the indentation device. In addition, the circuit isswitched to operate in an indentation mode. When switched to theindentation mode, the current producing circuit supplies a predeterminedamount of current through the coil. The predetermined amount of currentcorresponds to the amount of current needed to produce one of theaforementioned standard forces.

[0084] In particular, the predetermined amount of current creates amagnetic field in the actuation apparatus. This magnetic field, in turn,causes the movable central piece to push inwardly against the cornea viathe flexible membrane. Once the predetermined amount of current has beenapplied and a standard force presses against the cornea, it is necessaryto determine how far the movable central piece moved into the cornea.

[0085] Accordingly, when measurement of intraocular pressure byindentation is desired, the system of the present invention furtherincludes a distance detection arrangement for detecting a distancetraveled by the movable central piece, and a computation portion in thecalculation unit for determining intraocular pressure based on thedistance traveled by the movable central piece in applying thepredetermined amount of force.

[0086] Preferably, the computation portion is responsive to the currentproducing circuitry so that, once the predetermined amount of force isapplied, an output voltage from the distance detection arrangement isreceived by the computation portion. The computation portion then, basedon the displacement associated with the particular output voltage,determines intraocular pressure.

[0087] In addition, the present invention includes alternativeembodiments, as will be described hereinafter, for performingindentation-related measurements of the eye. Clearly, therefore, thepresent invention is not limited to the aforementioned exemplaryindentation device.

[0088] The aforementioned indentation device of the present inventionmay also be utilized to non-invasively measure hydrodynamics of an eyeincluding outflow facility. The method of the present inventionpreferably comprises several steps including the following:

[0089] According to a first step, an indentation device is placed incontact with the cornea. Preferably, the indentation device comprisesthe contact device of the present invention.

[0090] Next, at least one movable portion of the indentation device ismoved in toward the cornea using a first predetermined amount of forceto achieve indentation of the cornea. An intraocular pressure is thendetermined based on a first distance traveled toward the cornea by themovable portion of the indentation device during application of thefirst predetermined amount of force. Preferably, the intraocularpressure is determined using the aforementioned system for determiningintraocular pressure by indentation.

[0091] Next, the movable portion of the indentation device is rapidlyreciprocated in toward the cornea and away from the cornea at a firstpredetermined frequency and using a second predetermined amount of forceduring movement toward the cornea to thereby force intraocular fluid outfrom the eye. The second predetermined amount of force is preferablyequal to or more than the first predetermined amount of force. It isunderstood, however, that the second predetermined amount of force maybe less than the first predetermined amount of force.

[0092] The movable portion is then moved in toward the cornea using athird predetermined amount of force to again achieve indentation of thecornea. A second intraocular pressure is then determined based on asecond distance traveled toward the cornea by the movable portion of theindentation device during application of the third predetermined amountof force. Since intraocular pressure decreases as a result of forcingintraocular fluid out of the eye during the rapid reciprocation of themovable portion, it is generally understood that, unless the eye is sodefective that no fluid flows out therefrom, the second intraocularpressure will be less than the first intraocular pressure. Thisreduction in intraocular pressure is indicative of outflow facility.

[0093] Next, the movable portion of the indentation device is againrapidly reciprocated in toward the cornea and away from the cornea, butat a second predetermined frequency and using a fourth predeterminedamount of force during movement toward the cornea. The fourthpredetermined amount of force is preferably equal to or greater than thesecond predetermined amount of force; however, it is understood that thefourth predetermined amount of force maybe less than the secondpredetermined amount of force. Additional intraocular fluid is therebyforced out from the eye.

[0094] The movable portion is subsequently moved in toward the corneausing a fifth predetermined amount of force to again achieve indentationof the cornea. Thereafter, a third intraocular pressure is determinedbased on a third distance traveled toward the cornea by the movableportion of the indentation device during application of the fifthpredetermined amount of force.

[0095] The differences are then preferably calculated between the first,second, and third distances, which differences are indicative of thevolume of intraocular fluid which left the eye and therefore are alsoindicative of the outflow facility. It is understood that the differencebetween the first and last distances may be used, and in this regard, itis not necessary to use the differences between all three distances. Infact, the difference between any two of the distances will suffice.

[0096] Although the relationship between the outflow facility and thedetected differences varies when the various parameters of the methodand the dimensions of the indentation device change, the relationshipfor given parameters and dimensions can be easily determined by knownexperimental techniques and/or using known Friedenwald Tables.

[0097] Preferably, the method further comprises the steps of plottingthe differences between the first, second, and third distance to acreate a graph of the differences and comparing the resulting graph ofdifferences to that of a normal eye to determine if any irregularitiesin outflow facility are present.

[0098] Additionally, the present invention relates to the utilization ofa contact device placed on the front part of the eye in order to detectphysical and chemical parameters of the body as well as the non-invasivedelivery of compounds according to these physical and chemicalparameters, with signals preferably being transmitted continuously aselectromagnetic waves, radio waves, infrared and the like. One of theparameters to be detected includes non-invasive blood analysis utilizingchemical changes and chemical products that are found in the front partof the eye and in the tear film. The non-invasive blood analysis andother measurements are done using the system of my co-pending priorapplication, characterized as an intelligent contact lens system.

[0099] The word lens is used here to define an eyepiece which fitsinside the eye regardless of the presence of optical properties forcorrection of imperfect vision. The word intelligent used here defines alens capable of signal-detection and/or signal-transmission and/orsignal-reception and/or signal-emission and/or signal-processing andanalysis as well as the ability to alter physical, chemical, and orbiological variables. When the device is placed in other parts of thebody other than the eye, it is referred to as a contact device orintelligent contact device (ICD).

[0100] An alternative embodiment of the present invention will now bedescribed. The apparatus and method is based on a different and novelconcept originated by the inventor in which a transensor mounted in thecontact device laying on the cornea or the surface of the eye is capableof evaluating and measuring physical and chemical parameters in the eyeincluding non-invasive blood analysis. The alternative embodimentpreferably utilizes a transensor mounted in the contact device which ispreferably laying in contact with the cornea and is preferably activatedby the process of eye lid motion and/or closure of the eye lid. Thesystem preferably utilizes eye lid motion and/or closure of the eye lidto activate a microminiature radio frequency sensitive transensormounted in the contact device. The signal can be communicated by cable,but is preferably actively or passively radio telemetered to anexternally placed receiver. The signal can then be processed, analyzedand stored.

[0101] This eye lid force and motion toward the surface of the eye isalso capable to create the deformation of any transensor/electrodesmounted on the contact device. During blinking, the eye lids are in fullcontact with the contact device and the transensor's surface is incontact with the cornea/tear film and/or inner surface of the eye lidand/or blood vessels on the surface of the conjunctiva. It is understoodthat the transensor used for non-invasive blood analysis is continuouslyactivated when placed on the eye and do not need closure of the eyelidfor activation. It is understood that after a certain amount of time thecontact device will adhere to tissues in the conjunctiva optimizing flowof tissue fluid to sensors for measurement of blood components.

[0102] The present invention includes apparatus and methods thatutilizes a contact device laying on the surface of the eye calledintelligent contact lens (ICL) which provides means for transmittingphysiologic, physical, and chemical information from one location as forinstance living tissue on the surface of the eye to another remotelocation accurately and faithfully reproducing the event at thereceiver. In my prior copending application, the whole mechanism bywhich the eye lid activate transensors is described and a microminiaturepassive pressure-sensitive radio frequency transducer is disclosed tocontinuously measure intraocular pressure and eye fluid outflow facilitywith both open and closed eyes.

[0103] The present invention provides a new method and apparatus todetect physical and chemical parameters of the body and the eyeutilizing a contact device placed on the eye with signals beingtransmitted continuously as electromagnetic waves, radio waves, soundwaves, infrared and the like. Several parameters can be detected withthe invention including a complete non-invasive analysis of bloodcomponents, measurement of systemic and ocular blood flow, measurementof heart rate and respiratory rate, tracking operations, detection ofovulation, detection of radiation and drug effects, diagnosis of ocularand systemic disorders and the like. The invention also provides a newmethod and apparatus for somnolence awareness, activation of devices bydisabled individuals, a new drug delivery system and new therapy forocular and neurologic disorders, and treatment of cancer in the eye orother parts of the body, and an evaluation system for the overall healthstatus of an individual. The device of the present invention quantifiesnon-invasively the amount of the different chemical components in theblood using a contact device with suitable electrodes and membraneslaying on the surface of the eye and in direct contact with the tearfilm or surface of the eye, with the data being preferably transmittedutilizing radio waves, but alternatively sound waves, light waves, wire,or telephone lines can be used for transmission.

[0104] The system comprises a contact device in which a microminiatureradio frequency transensor, actively or passively activated, such asendoradiosondes, are mounted in the contact device which in turn ispreferably placed on the surface of the eye. A preferred method involvessmall passive radio telemetric transducers capable of detecting chemicalcompounds, electrolytes, glucose, cholesterol, and the like on thesurface of the eye. Besides using passive radio transmission orcommunication by cable, active radio transmission with activetransmitters contained a microminiature battery mounted in the contactdevice can also be used.

[0105] Several means and transensors can be mounted in the contactdevice and used to acquire the signal. Active radio transmitters usingtransensors which are energized by batteries or using cells that can berecharged in the eye by an external oscillator, and active transmitterswhich can be powered from a biologic source can also be used and mountedin the contact device. The preferred method to acquire the signalinvolves passive radio frequency transensors, which contain no powersource. They act from energy supplied to it from an external source. Thetransensor transmits signals to remote locations using differentfrequencies indicative of the levels of chemical and physicalparameters. These intraocular recordings can then be transmitted toremote extra ocular radio frequency monitor stations with the signalsent to a receiver for amplification and analysis. Ultrasonicmicro-circuits can also be mounted in the contact device and modulatedby sensors which are capable of detecting chemical and physical changesin the eye. The signal may be transmitted using modulated sound signalsparticularly under water because sound is less attenuated by water thanare radio waves. The sonic resonators can be made responsive to changesin temperature and voltage which correlate to the presence and level ofmolecules such as glucose and ions in the tear film.

[0106] Ocular and systemic disorders may cause a change in the pH,osmolarity, and temperature of the tear film or surface of the eye aswell as change in the tear film concentration of substances such asacid-lactic, glucose, lipids, hormones, gases, enzymes, inflammatorymediators, plasmin, albumin, lactoferrin, creatinin, proteins and so on.Besides pressure, outflow facility, and other physical characteristicsof the eye, the apparatus of the invention is also capable of measuringthe above physiologic parameters in the eye and tear film usingtransensor/electrodes mounted in the contact device. These changes inpressure, temperature, pH, oxygen level, osmolality, concentration ofchemicals, and so on can be monitored with the eyes opened or closed orduring blinking. In some instance such as with the evaluation of pH,metabolites, and oxygen concentration, the device does not neednecessarily eye lid motion because just the contact with the transensormounted in the contact device is enough to activate thetransensor/electrodes.

[0107] The presence of various chemical elements, gases, electrolytes,and pH of the tear film and the surface of the eye can be determined bythe use of suitable electrodes and a suitable permeable membrane. Theseelectrodes, preferably microelectrodes, can be sensitized by severalreacting chemicals which are in the tear film or the surface of the eye,in the surface of the cornea or preferably the vascularized areas in thesurface of the eye. The different chemicals and substances diffusethrough suitable permeable membranes sensitizing suitable sensors.Electrodes and sensors to measure the above compounds are available fromseveral manufacturers.

[0108] The level of oxygen can be measured in the eye with the contactdevice, and in this case just the placement of the contact device wouldbe enough to activate the system and eye lid motion and/or closure ofthe eye lid may not be necessary for its operation. Reversiblemechanical expansion methods, photometric, or electrochemical methodsand electrodes can be mounted in the device and used to detect acidityand gases concentration. Oxygen gas can also be evaluated according toits magnetic properties or be analyzed by micro-polarographic sensorsmounted in the contact device. Moreover, the same sensor can measuredifferent gases by changing the cathode potential. Carbon dioxide,carbon monoxide, and other gases can also be detected in a similarfashion.

[0109] Microminiature glass electrodes mounted in the contact device canbe used to detect divalent cations such as calcium, as well as sodiumand potassium ion and pH. Chloride-ion detector can be used to detectthe salt concentration in the tear film and the surface of the eye. Thesignal can be radio transmitted to a receiver and then to a screen forcontinuous recording and monitoring. This allows for the continuousnon-invasive measurement of electrolytes, chemicals and pH in the bodyand can be very useful in the intensive care unit setting.

[0110] A similar transensor can also be placed not in the eye, but incontact with other mucosas and secretions in the body, such as the oralmucosa, and the concentration of chemicals measured in the saliva oreven sweat or any other body secretion with signals being transmitted toa remote location via ultrasonic or radio waves and the like. However,due to the high concentration of enzymes in the saliva and in othersecretion, the electrodes and electronics could be detrimentallyaffected which would impact accuracy. Furthermore, there is a weakcorrelation between concentration of chemicals in body secretions andblood.

[0111] The tear fluid proves to be the most reliable location andindicator of the concentration of chemicals, both organic and inorganic,but other areas of the eye can be utilized to measure the concentrationof chemicals. The tear fluid and surface of the eye are the preferredlocation for these measurements because the tear film and aqueous humor(which can be transmitted through the intact cornea) can be consideredan ultrafiltrate of the plasma.

[0112] The apparatus and method of the present invention allows theleast traumatic way of measuring chemicals in the body without the needof needle stick and the manipulation of blood. For instance, this may beparticularly important as compared to drawing blood from infants becausethe results provided by the drawn blood sample may not be accurate.There is a dramatic change in oxygen and carbon dioxide levels becauseof crying, breath holding and even apnea spells that occur during theprocess of restraining the baby and drawing blood. Naturally, theability to painlessly measure blood components without puncturing thevessel is beneficial also to any adult who needs a blood work-up,patients with diabetes who need to check their glucose level on a dailybasis, and health care workers who would be less exposed to severediseases such as AIDS and hepatitis when manipulating blood. Patients inintensive care units would benefit by having a continuous painlessmonitoring of electrolytes, gases, and so on by non-invasive means usingthe intelligent contact lens system. Moreover, there is no time wastedtransporting the blood sample to the laboratory, the data is availableimmediately and continuously.

[0113] The different amounts of eye fluid encountered in the eye can beeasily quantified and the concentration of substances calibratedaccording to the amount of fluid in the eye. The relationship betweenthe concentration of chemical substances and molecules in the blood andthe amount of said chemical substances in the tear fluid can bedescribed mathematically and programmed in a computer since the tearfilm can be considered an ultrafiltrate of the plasma and diffusion ofchemicals from capillaries on the surface of the eye have a directcorrespondence to the concentration in the blood stream.

[0114] Furthermore, when the eyes are closed there is an equilibriumbetween the aqueous humor and the tear fluid allowing measurement ofglucose in a steady state and since the device can send signals throughthe intervening eyelid, the glucose can be continuously monitored inthis steady state condition. Optical sensors mounted in the contactdevice can evaluate oxygen and other gases in tissues and can be used todetect the concentration of compounds in the surface of the eye and thusnot necessarily have to use the tear film to measure the concentrationof said substances. In all instances, the signals can be preferablyradio transmitted to a monitoring station. Optical, acoustic,electromagnetic, micro-electromechanical systems and the like can bemounted in the contact device and allow the measurement of bloodcomponents in the tear film, surface of the eye, conjunctival vessels,aqueous humor, vitreous, and other intraocular and extraocularstructures.

[0115] Any substance present in the blood can be analyzed in this waysince as mentioned the fluid measured is a filtrate of the blood.Rapidly responding microelectrodes with very thin membranes can be usedto measure these substances providing a continuous evaluation. Forexample, inhaled anesthetics become blood gases and during an experimentthe concentration of anesthetics present in the blood could be evaluatedin the eye fluid. Anesthetics such as nitrous oxide and halothane can bereduced electrochemically at noble metal electrodes and the electrodescan be mounted in the contact device. Oxygen sensors can also used tomeasure the oxygen of the sample tear film. Measurement of oxygen andanesthetics in the blood has been performed and correlated well with theamount of the substances in the eye fluid with levels in the tear fluidwithin 85-95% of blood levels. As can be seen, any substances not onlythe ones naturally present, but also artificially inserted in the bloodcan be potentially measured in the eye fluid. A correction factor may beused to account for the differences between eye fluid and blood. Inaddition, the non-invasive measurement and detection by the ICL ofexogenous substances is a useful tool to law enforcement agents forrapidly testing and detecting drugs and alcohol.

[0116] The evaluation of systemic and ocular hemodynamics can beperformed with suitable sensors mounted in the contact device. Themeasurements of blood pulsations in the eye can be done throughelectrical means by evaluating changes in impedance. Blood flow rate canbe evaluated by several techniques including but not limited toultrasonic and electromagnetic meters and the signals then radiotransmitted to an externally placed device. For the measurement of bloodflow, the contact device is preferably placed in contact with theconjunctiva, either bulbar or palpebral, due to the fact that the corneais normally an avascular structure. Changing in the viscosity of bloodcan also be evaluated from a change in damping on a vibrating quartzmicro-crystal mounted in the contact device.

[0117] The apparatus of the invention may also measure dimension such asthe thickness of the retina, the amount of cupping in the optic nervehead, and so on by having a microminiature ultrasound device mounted inthe contact device and placed on the surface of the eye. Ultra sonictimer/exciter integrated circuits used in both continuous wave andpulsed bidirectional Doppler blood flowmeters are in the order fewmillimeters in length and can be mounted in the apparatus of theinvention.

[0118] For the measurement of hemodynamics, the contact device shouldpreferably be placed in contact with the conjunctiva and on top of ablood vessel. Doppler blood microflowmeters are available and continuouswave (CW) and pulsed Doppler instruments can be mounted in the contactdevice to evaluate blood flow and the signal radio transmitted to anexternal receiver. The Doppler flowmeters may also use ultrasonictransducers and these systems can be fabricated in miniature electronicpackages and mounted in the contact device with signals transmitted to aremote receiver.

[0119] Illumination of vessels, through the pupil, in the back of theeye can be used to evaluate blood flow velocity and volume or amount ofcupping (recess) in the optic nerve head. For this use the contactdevice has one or more light sources located near the center andpositioned in a way to reach the vessels that exit the optic nerve head,which are the vessels of largest diameter on the surface of the retina.A precise alignment of beam is possible because the optic nerve head issituated at a constant angle from the visual axis. Sensors can be alsopositioned on the opposite side of the illumination source and thereflected beam reaching the sensor. Multioptical filters can be housedin the contact device with the light signal converted to voltageaccording to the angle of incidence of reflected light.

[0120] Moreover, the intracranial pressure could be indirectly estimatedby the evaluation of changes and swelling in the retina and optic nervehead that occurs in these structures due to the increased intracerebralpressure. Fiber optics from an external light source or light sourcesbuilt in the contact device emit a beam of plane-polarized light fromone side at three o=clock position with the beam entering through thecornea and passing through the aqueous humor and exiting at the nineo=clock position to reach a photodetector. Since glucose can rotate theplane of polarization, the amount of optical rotation would becompared-to a second reference beam projected in the same manner butwith a wavelength that it is insensitive to glucose with the differencebeing indicative of the amount of glucose present in the aqueous humorwhich can be correlated to plasma glucose by using a correction factor.

[0121] A dielectric constant of several thousand can be seen in bloodand a microminiature detector placed in the contact device can identifythe presence of blood in the surface of the cornea. Moreover, bloodcauses the decomposition of hydrogen peroxide which promotes anexothermic reaction that can be sensed with a temperature-sensitivetransensor. Small lamps energized by an external radio-frequency fieldcan be mounted in the contact device and photometric blood detectors canbe used to evaluate the presence of blood and early detection ofneovascularization in different parts of the eye and the body.

[0122] A microminiature microphone can be mounted in the contact deviceand sounds from the heart, respiration, flow, vocal and the environmentcan be sensed and transmitted to a receiver. In cases of abnormal heartrhythm, the receiver would be carried by the individual and will havemeans to alert the individual through an alarm circuit either by lightor sound signals of the abnormality present. Changes in heart beat canbe detected and the patient alerted to take appropriate action.

[0123] The contact device can also have elements which produce andradiate recognizable signals and this procedure could be used to locateand track individuals, particularly in military operations. A permanentmagnet can also be mounted in the contact device and used for trackingas described above.

[0124] Life threatening injuries causing change in heart rhythm andrespiration can be detected since the cornea pulsates according toheartbeat. Motion sensitive microminiature radio frequency transensorscan be mounted in the contact device and signals indicative of injuries'can be radio transmitted to a remote station particularly for monitoringduring combat in military operations.

[0125] In rocket or military operations or in variable g situations, theparameters above can be measured and monitored by utilizing materials inthe transensor such as light aluminum which are less sensitive togravitational and magnetic fields. Infrared emitters can be mounted inthe contact device and used to activate distinct photodetectors byocular commands such as in military operations where fast action isneeded without utilizing hand movement.

[0126] Spinal cord injuries have lead thousands of individuals tocomplete confinement in a wheel chair. The most unfortunate situationoccurs with quadriplegic individuals who virtually only have usefulmovement of their mouth and eyes. The apparatus of the invention allowsthese individuals to use their remaining movement ability to become moreindependent and capable of indirect manipulation of a variety ofhardware. In this embodiment, the ICL uses blinking or closure of theeyes to activate remotely placed receptor photodiodes through theactivation of an LED drive coupled with a pressure sensor.

[0127] The quadriplegic patient focuses on a receptor photo diode andcloses their eyes for 5 seconds, for example. The pressure exerted bythe eyelid is sensed by the pressure sensor which is coupled with atiming chip. If the ICL is calibrated for 5 sec, after this amount oftime elapses with eyes closed, the LED drive activates the LED whichemits infrared light though the intervening eyelid tissue reachingsuitable receptor photodiodes or suitable optical receivers connected toa power on or off circuit. This allows quadriplegics to turn on, turnoff, or manipulate a variety of devices using eye motion. It isunderstood that an alternative embodiment can use more complexintegrated circuits connected by fine wires to the ICL placed on the eyein order to perform more advanced functions such as using LED=s ofdifferent wavelengths.

[0128] Another embodiment according to the present invention includes asomnolence alert device using eye motion to detect premonitory signs ofsomnolence related to a physiologic condition called Bell phenomena inwhich the eye ball moves up and slightly outwards when the eyes areclosed. Whenever an individual starts to fall asleep, the eye lid comesdown and the eyes will move up.

[0129] A motion or pressure sensor mounted in the superior edge of theICL will cause, with the Bell phenomena, a movement of the contactdevice upwards. This movement of the eye would position the pressuresensitive sensor mounted in the contact device against the superiorcul-de-sac and the pressure created will activate the sensor whichmodulates a radio transmitter. The increase in pressure can be timed andif the pressure remains increased for a certain length of timeindicating closed eyes, an alarm circuit is activated. The signal wouldthen be transmitted to a receiver coupled with an alarm circuit andspeaker creating a sound signal to alert the individual at the initialindication of falling asleep. Alternatively, the pressure sensor can bepositioned on the inferior edge of the ICL and the lack of pressure inthe inferiorly placed sensor would activate the circuit as describedabove.

[0130] It is also understood that other means to activate a circuit inthe contact device such as closing an electric circuit due to motion orpressure shift in the contact device which remotely activate an alarmcan be used as a somnolence awareness device. It is also understood thatany contact device with sensing elements capable of sensing Bellphenomena can be used as a somnolence awareness device. This system,device and method are an important tool in diminishing car accidents andmachinery accidents by individuals who fall sleep while operatingmachinery and vehicles.

[0131] If signs of injury in the eye are detected, such as increasedintraocular pressure (IOP), the system can be used to release medicationwhich is placed in the cul-de-sac in the lower eye lid as a reservoir orpreferably the contact lens device acts as a reservoir for medications.A permeable membrane, small fenestrations or a valve like system withmicro-gates, or micro-electronic systems housed in the contact devicestructure could be electrically, magnetically, electronically, oroptically activated and the medication stored in the contact devicereleased. The intelligent lenses can thus be used as non-invasive drugdelivery systems. Chemical composition of the tear film, such as thelevel of electrolytes or glucose, so that can be sensed and signalsradio transmitted to drug delivery pumps carried by the patient so thatmedications can be automatically delivered before symptoms occur.

[0132] A part of the contact transducer can also be released, forinstance if the amount of enzymes increases. The release of part of thecontact device could be a reservoir of lubricant fluid which willautomatically be released covering the eye and protecting it against theinsulting element. Any drugs could be automatically released in asimilar fashion or through transmission of signal to the device.

[0133] An alternative embodiment includes the contact device which has acompartment filled with chemical substances or drugs connected to athread which keeps the compartments sealed. Changes in chemicals in thetear fluid or the surface of the eye promote voltage increases whichturns on a heater in the circuit which melts the thread allowingdischarge of the drug housed in the compartment such as insulin if thereis an increase in the levels of glucose detected by the glucose sensor.

[0134] To measure temperature, the same method and apparatus applies,but in this case the transmitter is comprised of a temperature-sensitiveelement. A microminiature temperature-sensitive radio frequencytransensor, such as thermistor sensor, is mounted in the contact devicewhich in turn is placed on the eye with signals preferably radiotransmitted to a remote station. Changes in temperature and body heatcorrelate with ovulation and the thermistor can be mounted in thecontact device with signals telemetered to a remote station indicatingoptimum time for conception.

[0135] The detection and transmission to remote stations of changes intemperature can be used on animals for breeding purposes. Theintelligent contact lens can be placed on the eye of said animals andcontinuous monitoring of ovulation achieved. When this embodiment isused, the contact device with the thermistor is positioned so that itlodges against the palpebral conjunctiva to measure the temperature atthe palpebral conjunctiva. Monitoring the conjunctiva offers theadvantages of an accessible tissue free of keratin, a capillary levelclose to the surface, and a tissue layer vascularized by the samearterial circulation as the brain. When the lids are closed, the thermalenvironment of the cornea is exclusively internal with passiveprevention of heat loss during a blink and a more active heat transferduring the actual blink.

[0136] In carotid artery disease due to impaired blood supply to theeye, the eye has a lower temperature than that of the fellow eye whichindicates a decreased blood supply. If a temperature difference greaterthan normal exists between the right and left eye, then there is anasymmetry in blood supply. Thus, this embodiment can provide informationrelated to carotid and central nervous system vascular disorders.Furthermore, this embodiment can provide information concerningintraocular tumors such as melanoma. The area over a malignant melanomahas an increase in temperature and the eye harboring the malignantmelanoma would have a higher temperature than that of the fellow eye. Inthis embodiment the thermistor is combined with a radio transmitteremitting an audio signal frequency proportional to the temperature.

[0137] Radiation sensitive endoradiosondes are known and can be used inthe contact device to measure the amount of radiation and the presenceof radioactive corpuscules in the tear film or in front of the eye whichcorrelates to its presence in the body. The amount of hydration andhumidity of the eye can be sensed with an electrical discharge andvariable resistance moisture sensor mounted in the contact device.Motion and deceleration can be detected by a mounted accelerometer inthe contact device. Voltages accompanying the function of the eye,brain, and muscles can be detected by suitable electrodes mounted in thedevice and can be used to modulate the frequency of the transmitter. Inthe case of transmission of muscle potentials, the contact device isplaced not on the cornea, but next to the extraocular muscle to beevaluated and the signals remotely transmitted. A fixed frequencytransmitter can be mounted in the contact device and used as a trackingdevice which utilizes a satellite tracking system by noting thefrequency received from the fixed frequency transmitter to a passingsatellite

[0138] A surface electrode mounted in the contact device may beactivated by optical or electromagnetic means in order to increase thetemperature of the eye. This increase in temperature causes a dilationof the capillary bed and can be used in situations in which there ishypoxia (decreased oxygenation) in the eye. The concept and apparatuscalled heat stimulation transmission device (HSTD) is based upon myexperiments and in the fact that the eye has one of largest blood supplyper gram of tissue in the body and has the unique ability to beoverpefused when there is an increase in temperature. The blood flow tothe eye can thus be increased with a consequent increase in the amountof oxygen. The electrode can be placed in any part of the eye, inside oroutside, but is preferably placed on the most posterior part of the eye.The radio frequency activated heating elements can be externally placedor surgically implanted according to the area in need of increase in theamount of oxygen in the eye. It is understood that the same heatingelements could be placed or implanted in other parts of the body.Naturally, means that promote an increase in temperature of the eyewithout using electrodes can be used as long as the increase intemperature is sufficient to increase blood flow without promoting anyinjury.

[0139] The amount of increase varies from individual to individual andaccording to the status of the vascular bed of the eye. The increase intemperature of blood in the eye raises its oxygen level about 6% pereach one degree Celsius of increase in temperature allowing precisequantification of the increase in oxygen by using a thermistor whichsimultaneously indicates temperature, or alternatively an oxygen sensorcan be used in association with the heating element and actual amount ofincrease in oxygen detected.

[0140] This increase in blood flow can be timed to occur atpredetermined hours in the case of chronic hypoxia such as in diabetes,retinal degenerations, and even glaucoma. These devices can beexternally placed or surgically implanted in the eye or other parts ofthe body according to the application needed.

[0141] Another embodiment is called over heating transmission device(OHTD) and relates to a new method and apparatus for the treatment oftumors in the eye or any other part of the body by using surgicallyimplanted or externally placed surface electrodes next to a tumor withthe electrodes being activated by optical or electromagnetic means inorder to increase the temperature of the cancerous tissue untilexcessive localized heat destroys the tumor cells. These electrodes canbe packaged with a thermistor and the increase in temperature sensed bythe thermistor with the signal transmitted to a remote station in orderto evaluate the degree of temperature increase.

[0142] Another embodiment concerning therapy of eye and systemicdisorders include a neuro-stimulation transmission device (NSTD) whichrelates to a system in which radio activated micro-photodiodes or/andmicro-electric circuits and electrodes are surgically implanted orexternally placed on the eye or other parts of the body such as thebrain and used to electrically stimulate non-functioning neural ordegenerated neural tissue in order to treat patients with retinaldegeneration, glaucoma, stroke, and the like. Multiple electrodes can beused in the contact device, placed on the eye or in the brain forelectrical stimulation of surrounding tissues with consequentregeneration of signal transmission by axonal and neural cells andregeneration of action potential with voltage signals being transmittedto a remote station.

[0143] Radio and sonic transensors to measure pressure, electricalchanges, dimensions, acceleration, flow, temperature, bioelectricactivity and other important physiologic parameters and power switchesto externally control the system have been developed and are suitablesystems to be used in the apparatus of the invention. The sensors can beautomatically turned on and off with power switches externallycontrolling the intelligent contact lens system. The use of integratedcircuits and advances occurring in transducer, power source, and signalprocessing technology allow for extreme miniaturization of thecomponents which permits several sensors to be mounted in one contactdevice. For instance, typical resolutions of integrated circuits are inthe order of a few microns and very high density circuit realization canbe achieved. Radio frequency and ultrasonic microcircuits are availableand can be used and mounted in the contact device. A number of differentultrasonic and pressure transducers are also available and can be usedand mounted in the contact device.

[0144] Technologic advances will occur which allow full and novelapplications of the apparatus of the invention such as measuringenzymatic reactions and DNA changes that occur in the tear fluid orsurface of the eye, thus allowing an early diagnosis of disorders suchas cancer and heart diseases. HIV virus is present in tears and AIDScould be detected with the contact device by sensors coated withantibodies against the virus which would create a photochemical reactionwith appearance of calorimetric reaction and potential shift in thecontact device with subsequent change in voltage or temperature that canbe transmitted to a monitoring station.

[0145] A variety of other pathogens could be identified in a similarfashion. These signals can be radio transmitted to a remote station forfurther signal processing and analysis. In the case of the appearance offluorescent light, the outcome could be observed on a patient=s eyesimply by illuminating the eye with light going through a cobalt filterand in this embodiment the intelligent contact lens does not need tonecessarily have signals transmitted to a station.

[0146] The system further comprises a contact device in which amicrominiature gas-sensitive, such as oxygen-sensitive, radio frequencytransensor is mounted in the contact device which in turn is placed onthe cornea and/or surface of the eye. The system also comprises acontact device in which a microminiature blood velocity-sensitive radiofrequency transensor is mounted in the contact device which in turn isplaced on the conjunctiva and is preferably activated by eye lid motionand/or closure of the eye lid. The system also comprises a contactdevice in which a radio frequency transensor capable of measuring thenegative resistance of nerve fibers is mounted in the contact devicewhich in turn is preferably placed on the cornea and/or surface of theeye. By measuring the electrical resistance, the effects ofmicroorganisms, drugs, poisons and anesthetics can be evaluated. Thesystem also comprises a contact device in which a microminiatureradiation-sensitive radio frequency transensor is mounted in the contactdevice which in turn is preferably placed on the cornea.

[0147] The contact device preferably includes a rigid or flexibleannular member in which a transensor is mounted in the device. Thetransensor is positioned in a way to allow passage of light through thevisual axis. The annular member preferably includes an inner concavesurface shaped to match an outer surface of the eye and having one ormore holes defined therein in which transensors are mounted. It isunderstood that the contact device conforms in general shape to thesurface of the eye with its dimensions and size chosen to achieveoptimal comfort level and tolerance. It is also understood that thecurvature and shape of the contact device is chosen to intimately andaccurately fit the contact device to the surface of the eye foroptimization of sensor function. The surface of the contact device canbe porous or microporous as well as with mircro-protuberances on thesurface. It is also understood that fenestrations can be made in thecontact device in order to allow better oxygenation of the cornea whenthe device is worn for a long period of time. It is also understood thatthe shape of the contact device may include a ring-like or band-likeshape without any material covering the cornea. It is also understoodthat the contact device may have a base down prism or truncated edge forbetter centration. It is also understood that the contact devicepreferably has a myoflange or a minus carrier when a conventionalcontact lens configuration is used. It is also understood that aneliptical, half moon shape or the like can be used for placement underthe eyelid. It is understood that the contact device can be made withsoft of hard material according to the application needed. It is alsounderstood that an oversized corneal scleral lens covering the wholeanterior surface of the eye can be used as well as hourglass shapedlenses and the like. It is understood also that the external surface ofthe contact device can be made with polymers which increases adherenceto tissues or coating which increases friction and adherence to tissuesin order to optimize fluid passage to sensors when measuring chemicalcomponents. It is understood that the different embodiments which areused under the eyelids are shaped to fit beneath the upper and/oreyelids as well as to fit the upper or lower cul-de-sac.

[0148] The transensor may consist of a passive or active radio frequencyemitter, or a miniature sonic resonator, and the like which can becoupled with miniature microprocessor mounted in the contact device. Thetransensors mounted in the contact device can be remotely driven byultrasonic waves or alternatively remotely powered by electromagneticwaves or by incident light. They can also be powered by microminiaturelow voltage batteries which are inserted into the contact device.

[0149] As mentioned, preferably the data is transmitted utilizing radiowaves, sound waves, light waves, by wire, or by telephone lines. Thedescribed techniques can be easily extrapolated to other transmissionsystems. The transmitter mounted in the contact device can use thetransmission links to interconnect to remote monitoring sites. Thechanges in voltage or voltage level are proportional to the values ofthe biological variables and this amplified physiologic data signal fromthe transducers may be frequency modulated and then transmitted to aremote external reception unit which demodulates and reconstitutes thetransmitted frequency modulated data signal preferably followed by a lowpass filter with the regeneration of an analog data signal withsubsequent tracing on a strip-chart recorder.

[0150] The apparatus of the invention can also utilize a retransmiter inorder to minimize electronic components and size of the circuit housedin the contact device. The signal from a weak transmitter can beretransmitted to a greater distance by an external booster transmittercarried by the subject or placed nearby. It is understood that a varietyof noise destruction methods can be used in the apparatus of theinvention.

[0151] Since the apparatus of the invention utilizes externally placedelements on the surface of the eye that can be easily retrieved, thereis no tissue damage due to long term implantation and if drift occurs itis possible to recalibrate the device. There are a variety of formatsthat can be used in the apparatus of the invention in which biologicdata can be encoded and transmitted. The type of format for a givenapplication is done according to power requirement, circuit complexity,dimensions and the type of biologic data to be transmitted. The generallayout of the apparatus preferably includes an information source with avariety of biological variables, a transducer, a multiplexer, atransmitter, a transmission path and a transmission medium through whichthe data is transmitted preferably as a coded and modulated signal.

[0152] The apparatus of the invention preferably includes a receiverwhich receives the coded and modulated signal, an amplifier and low passfilter, a demultiplexer, a data processing device, a display andrecording equipment, and preferably an information receiver, a CPU, amodem, and telephone connection. A microprocessor unit containing anautodialing telephone modem which automatically transmits the data overthe public telephone network to a hospital based computer system can beused. It is understood that the system may accept digitally codedinformation or analog data.

[0153] When a radio link is used, the contact device houses a radiofrequency transmitter which sends the biosignals to a receiver locatednearby with the signals being processed and digitized for storage andanalysis by microcomputer systems. When the apparatus of the inventiontransmits data using a radio link, a frequency carrier can be modulatedby a subcarrier in a variety of ways: amplitude modulation (AM),frequency modulation (FM), and code modulation (CM). The subcarriers canbe modulated in a variety of ways which includes AM, FM, pulse amplitudemodulation (PAM), pulse duration modulation (PDM), pulse positionmodulation (PPM), pulse code moduation (PCM), delta modulation (DM), andthe like.

[0154] It is understood that the ICL structure and thetransducer/transmitter housing are made of material preferablytransparent to radio waves and the electronic components coated withmaterials impermeable to fluids and salts and the whole unit encased ina biocompatable material. The electronics, sensors, and battery(whenever an active system is used), are housed in the contact deviceand are hermetically sealed against fluid penetration. It is understoodthat sensors and suitable electrodes such as for sensing chemicals, pHand the like, will be in direct contact with the tear fluid or thesurface of the eye. It is also understood that said sensors, electrodesand the like may be covered with suitable permeable membranes accordingto the application needed. The circuitry and electronics may be encasedin wax such as beeswax or paraffin which is not permeable to body fluid.It is understood that other materials can be used as a moisture barrier.It is also understood that various methods and materials can be used aslong as there is minimal frequency attenuation, insulation, andbiocompatibility. The components are further encased by biocompatiblematerials as the ones used in conventional contact lenses such asHydrogel, silicone, flexible acrylic, sylastic, or the like.

[0155] The transmitter, sensors, and other components can be mountedand/or attached to the contact device using any known attachmenttechniques, such as gluing, heat-bonding, and the like. The intelligentcontact lens can use a modular construction in its assembly as to allowtailoring the number of components by simply adding previouslyconstructed systems to the contact device.

[0156] It is understood that the transmission of data can beaccomplished using preferably radio link, but other means can also beused. The choice of which energy form to be used by the ICL depends onthe transmission medium and distance, channel requirement, size oftransmitter equipment and the like. It is understood that thetransmission of data from the contact device by wire can be used but hasthe disadvantage of incomplete freedom from attached wires. However, theconnection of sensors by wires to externally placed electronics,amplifiers, and the like allows housing of larger sensors in the contactdevice when the application requires as well as the reduction ofmechanical and electrical connections in the contact device. Thetransmission of data by wire can be an important alternative when thereis congested space due to sensors and electronics in the contact device.It is understood that the transmission of data in water from the contactdevice can be preferably accomplished using sound energy with a receiverpreferably using a hydrophone crystal followed by conventional audiofrequency FM decoding.

[0157] It is also understood that the transmission of data from thecontact device can be accomplished by light energy as an alternative toradio frequency radiation. Optical transmission of signals using allsorts of light such as visible, infrared, and ultraviolet can be used asa carrier for the transmission of data preferably using infrared lightas the carrier for the transmission system. An LED can be mounted in thecontact device and transmit modulated signals to remotely placedreceivers with the light emitted from the LED being modulated by thesignal. When using this embodiment, the contact device in the receiverunit has the following components: a built in infrared light emitter(950 nm), an infrared detector, decoder, display, and CPU. Prior totransmission, the physiologic variables found on the eye or tear fluidare multiplexed and encoded by pulse interval modulation, pulsefrequency modulation, or the like. The infrared transmitter then emitsshort duration pulses which are sensed by a remotely placed photodiodein the infrared detector which is subsequently decoded, processed, andrecorded. The light transmitted from the LED is received at the opticalreceiver and transformed into electrical signals with subsequentregeneration of the biosignals. Infrared light is reflected quite wellincluding surfaces that do not reflect visible light and can be used inthe transmission of physiological variables and position/motionmeasurement. This embodiment is particularly useful when there islimitations in bandwidth as in radio transmission. Furthermore, thisembodiment may be quite useful with closed eyes since the light can betransmitted through the skin of the eyelid.

[0158] It is also understood that the transmission of data from thecontact device can be accomplished by the use of sound and ultrasoundbeing the preferred way of transmission underwater since sound is lessstrongly attenuated by water than radio waves. The information istransmitted using modulated sound signals with the sound waves beingtransmitted to a remote receiver. There is a relatively high absorptionof ultrasonic energy by living tissues, but since the eye even whenclosed has a rather thin intervening tissue the frequency of theultrasonic energy is not restricted. However, soundwaves are not thepreferred embodiment since they can take different paths from theirsource to a receiver with multiple reflections that can alter the finalsignal. Furthermore, it is difficult to transmit rapidly changingbiological variables because of the relatively low velocity of sound ascompared to electromagnetic radiation. It is possible though to easilymount an ultrasonic endoradiosonde in the contact device such as fortransmitting pH values or temperature. An ultrasonic booster transmitterlocated nearby or carried by the subject can be used to transmit thesignal at a higher power level. An acoustic tag with a magnetic compasssensor can be used with the information acoustically telemetered to asector scanning sonar.

[0159] A preferred embodiment of the invention consists of electrodes,FM transmitter, and a power supply mounted in the contact device.Stainless steel micro cables are used to connect the electronics to thetransducers to the battery power supply. A variety of amplifiers and FMtransmitters including Colpitts oscillator, crystal oscillators andother oscillators preferably utilizing a custom integrated circuitapproach with ultra density circuitry can be used in the apparatus ofthe invention.

[0160] Several variables can be simultaneously transmitted usingdifferent frequencies using several transmitters housed in the contactdevice. Alternatively, a single transmitter (3 channel transmitter) cantransmit combined voltages to a receiver, with the signal beingsubsequently decoded, separated into three parts, filtered andregenerated as the three original voltages (different variables such asglucose level, pressure and temperature). A multiple channel systemincorporating all signal processing on a single integrated circuitminimizes interconnections and can be preferably mounted in theapparatus of the invention when multiple simultaneous signaltransmission is needed such as transmitting the level of glucose,temperature, bioelectrical, and pressure. A single-chip processor can becombined with a logic chip to also form a multichannel system for theapparatus of the invention allowing measurement of several parameters aswell as activation of transducers.

[0161] It is understood that a variety of passive, active, and inductivepower sources can be used in the apparatus of the invention. The powersupply may consist of micro batteries, inductive power link, energy frombiological sources, nuclear cells, micro power units, fuel cells whichuse glucose and oxygen as energy sources, and the like. The type ofpower source is chosen according to the biological or biophysical eventto be transmitted.

[0162] A variety of signal receivers can be used such a frame aerialconnected to a conventional FM receiver from which the signal isamplified decoded and processed. Custom integrated circuits will providethe signal processing needed to evaluate the parameters transmitted suchas temperature, pressure flow dimensions, bioelectrical activity,concentration of chemical species and the like. The micro transducers,signal processing electronics, transmitters and power source can bebuilt in the contact device.

[0163] Power for the system may be supplied from a power cell activatedby a micropower control switch contained in the contact device or can beremotely activated by radio frequency means, magnetic means and thelike. Inductive radio frequency powered telemetry in which the same coilsystem used to transfer energy is used for the transmission of datasignal can be used in the apparatus of the invention. The size of thesystem relates primarily to the size of the batteries and thetransmitter. The size of conventional telemetry systems are proportionalto the size of the batteries because most of the volume is occupied bybatteries. The size of the transmitter is related to the operatingfrequency with low frequencies requiring larger components than higherfrequency circuits. Radiation at high frequencies are more attenuatedthan lower frequencies by body tissues. Thus a variety of systemsimplanted inside the body requires lower frequency devices andconsequently larger size components in order for the signal to be lessatenuated. Since the apparatus of the invention is placed on the surfaceof the eye there is little to no attenuation of signals and thus higherfrequency small devices can be used. Furthermore, very small batteriescan be used since the contact device can be easily retrieved and easilyreplaced. The large volume occupied by batteries and power sources inconventional radio telemetry implantable devices can be extremelyreduced since the apparatus of the invention is placed externally on theeye and is of easy access and retrieval, and thus a very small batterycan be utilized and replaced whenever needed.

[0164] A variety of system assemblies can be used but the densest systemassembly is preferred such as a hybrid assembly of custom integratedcircuits which permits realization of the signal processing needed forthe applications. The typical resolution of such circuits are in theorder of a few microns and can be easily mounted in the contact device.A variety of parameters can be measured with one integrated circuitwhich translates the signals preferably into a transmission bandwidth.Furthermore, a variety of additional electronics and a complementarymetal oxide semiconductor (CMOS) chip can be mounted in the apparatus ofthe invention for further signal processing and transmission.

[0165] The micropower integrated circuits can be utilized with a varietyof transmitter modalities mounted in the intelligent contact lensincluding radio links, ultrasonic link and the like. A variety of otherintegrated circuits can be mounted in the contact device such as signalprocessors for pressure and temperature, power switches for externalcontrol of implanted electronics and the like. Pressure transducers suchas a capacitive pressure transducer with integral electronics for signalprocessing can be incorporated in the same silicon structure and can bemounted in the contact device. Evolving semiconductor technology andmore sophisticated encoding methods as well as microminiature integratedcircuits amplifiers and receivers are expected to occur and can behoused in the contact device. It is understood that a variety oftransmitters, receivers, and antennas for transmitting and receivingsignals in telemetry can be used in the apparatus of the invention, andhoused in the contact device and/or placed remotely for receiving,processing, and analyzing the signal.

[0166] The fluid present on the front surface of the eye covering theconjunctiva and cornea is referred as the tear film or tear fluid. Closeto 100% of the tear film is produced by the lacrimal gland and secretedat a rate of 2 μl/min. The volume of the tear fluid is approximately 10μ1. The layer of tear fluid covering the cornea is about 8-10 μm inthickness and the tear fluid covering the conjunctiva is about 15 μmthick. The pre-corneal tear film consists of three layers: a thin lipidlayer measuring about 0.1 μm consisting of the air tear interface, amucin layer measuring 0.03 μm which is in direct contact with thecorneal epithelium, and finally the remaining layer is the thick aqueouslayer which is located between the lipid and mucin layer. The aqueouslayer is primarily derived from the secretions of the lacrimal gland andits chemical composition is very similar to diluted blood with a reducedprotein content and slightly greater osmotic pressure. The secretion andflow of tear fluid from the lacrimal gland located in thesupero-temporal quadrant with the subsequent exit through the lacrimalpuncta located in the infero-medial quadrant creates a continuous flowof tear fluid providing the ideal situation by furnishing a continuoussupply of substrate for one of the stoichiometric reactions which is thesubject of a preferred embodiment for evaluation of glucose levels. Themain component of the tear fluid is the aqueous layer which is anultrafiltrate of blood containing electrolytes such as sodium,potassium, chloride, bicarbonate, calcium, and magnesium as well asamino acids, proteins, enzymes, DNA, lipids, cholesterol, glycoproteins,immunoglobulins, vitamins, minerals and hormones. Moreover, the aqueouslayer also holds critical metabolites such as glucose, urea,catecholamines, and lactate, as well as gases such as oxygen and carbondioxide. Furthermore, any exogenous substances found in the blood streamsuch as drugs, radioactive compounds and the like are present in thetear fluid. Any compound present in the blood can potentiallynoninvasively be evaluated with the apparatus of the invention with thedata transmitted and processed at a remotely located station.

[0167] According to one preferred embodiment of the invention, thenon-invasive analysis of glucose levels will be described: GlucoseDetection:—The apparatus and methods for measurement of blood componentsand chemical species in the tear fluid and/or surface of the eye isbased on electrodes associated with enzymatic reactions providing anelectrical current which can be radio transmitted to a remote receiverproviding continuous data on the concentration of species in the tearfluid or surface of the eye. The ICL system is preferably based on adiffusion limited sensors method that requires no reagents ormechanical/moving parts in the contact device. The preferred method andapparatus of the glucose detector using ICL uses the enzyme glucoseoxidase which catalyze a reaction involving glucose and oxygen inassociation with electrochemical sensors mounted in the contact devicethat are sensitive to either the product of the reaction, an endogenouscoreactant, or a coupled electron carrier molecule such as theferrocene-mediated glucose sensors, as well as the directelectrochemical reaction of glucose at the contact devicemembrane-covered catalytic metal electrode.

[0168] Glucose and oxygen present in the tear fluid either derived fromthe lacrimal gland or diffused from vessels on the surface of the eyewill diffuse into the contact device reaching an immobilized layer ofenzyme glucose oxidase mounted in the contact device. Successfuloperation of enzyme electrodes demand constant transport of thesubstrate to the electrode since the substrate such as glucose andoxygen are consumed enzymatically. The ICL is the ideal device for usingenzyme electrodes since the tear fluid flows continuously on the surfaceof the eye creating an optimal environment for providing substrate forthe stoichiometric reaction. The ICL besides being a noninvasive systemsolves the critical problem of sensor lifetime which occurs with anysensors that are implanted inside the body. The preferred embodimentrefers to amperometric glucose biosensors with the biosensors based onbiocatalytic oxidation of glucose in the presence of the enzyme oxidase.This is a two step process consisting of enzymatic oxidation of glucoseby glucose oxidase in which the co-factor flavin-adenine dinucleotide(FAD) is reduced to FADH₂ followed by oxidation of the enzyme co-factorby molecular oxygen with formation of hydrogen peroxide.

[0169] With catalase enzyme the overall reaction is

[0170] glucose+2O₂° gluconic acid

[0171] Glucose concentration can be measured either by electrochemicaldetection of an increase of the anodic current due to hydrogen peroxide(product of the reaction) oxidation or by detection of the decrease inthe cathodic current due to oxygen (co-reactant) reduction. The ICLglucose detection system preferably has an enzyme electrode in contactwith the tear fluid and/or surface of the eye capable of measuring theoxidation current of hydrogen peroxide created by the stoichiometricconversion of glucose and oxygen in a layer of glucose oxidase mountedinside the contact device. The ICL glucose sensor is preferablyelectrochemical in nature and based on a hydrogen peroxide electrodewhich is converted by immobilized glucose oxidase which generates adirect current depending on the glucose concentration of the tear fluid.

[0172] The glucose enzyme electrode of the contact device responds tochanges in the concentration of both glucose and oxygen, both of whichare substrates of the immobilized enzyme glucose oxidase. It is alsounderstood that the sensor in the contact device can be made responsiveto glucose only by operating in a differential mode. The enzymaticelectrodes built in the contact device are placed in contact with thetear fluid or the surface of the eye and the current generated by theelectrodes according to the stoichiometric conversion of glucose, aresubsequently converted to a frequency audio signal and transmitted to aremote receiver, with the current being proportional to the glucoseconcentration according to calibration factors.

[0173] The signals can be transmitted using the various transmissionsystems previously described with an externally placed receiverdemodulating the audio frequency signal to a voltage and the glucoseconcentration being calculated from the voltage and subsequentlydisplayed on a LED display. An interface card can be used to connect thereceiver with a computer for further signal processing and analysis.During oxidation of glucose by glucose oxidase an electrochemicallyoxidable molecule or any other oxidable species generated such ashydrogen peroxide can be detected amperometrically as a current by theelectrodes. A preferred embodiment includes a tree electrode setupconsisting of a working electrode (anode) and auxiliary electrode(cathode) and a reference electrode connected to an amperometricdetector. It should be noted though, that a glucose sensor couldfunction well using two electrodes. When appropriate voltage differenceis applied between the working and auxiliary electrode, hydrogenperoxide is oxidized on the surface of the working electrode whichcreates a measurable electric current. The intensity of the currentgenerated by the sensor is proportional to the concentration of hydrogenperoxide which is proportional to the concentration of glucose in thetear film and the surface of the eye.

[0174] A variety of materials can be used for the electrodes such assilver/silver chloride coded cathodes. Anodes may be preferablyconstructed as a platinum wire coated with glucose oxidase or preferablycovered by a immobilized glucose oxidase membrane. Several possibleconfigurations for sensors using amperometric enzyme electrodes whichinvolves detection of oxidable species can be used in the apparatus ofthe invention. A variety of electrodes and setups can be used in thecontact device which are capable of creating a stable working potentialand output current which is proportional to the concentration of bloodcomponents in the tear fluid and surface of the eye. It is understoodthat a variety of electrode setups for the amperometric detection ofoxidable species can be accomplished with the apparatus of theinvention. It is understood that solutions can be applied to the surfaceof the electrodes to enhance transmission.

[0175] Other methods which use organic mediators such as ferrocene whichtransfers electrons from glucose oxidase to a base electrode withsubsequent generation of current can be utilized. It is also understoodthat needle-type glucose sensors can be placed in direct contact withthe conjunctiva or encased in a contact device for measurement ofglucose in the tear fluid. It is understood that any sensor capable ofconverting a biological variable to a voltage signal can be used in thecontact device and placed on the surface of the eye for measurement ofthe biological variables. It is understood that any electrodeconfiguration which measures hydrogen peroxide produced in the reactioncatalysed by glucose oxidase can be used in the contact device formeasurement of glucose levels. It is understood that the followingoxygen based enzyme electrode glucose sensor can be used in theapparatus of the invention which is based on the principal that theoxygen not consumed by-the enzymatic reactions by catalase enzyme iselectrochemically reduced at an oxygen sensor producing a glucosemodulated oxygen dependent current. This current is compared to acurrent from a similar oxygen sensor without enzymes.

[0176] It is understood that the sensors are positioned in a way tooptimize the glucose access to the electrodes such as by creating microtraumas to increase diffusion of glucose across tissues and capillarywalls, preferably positioning the sensors against vascularized areas ofthe eye. In the closed eye about two-thirds of oxygen and glucose comesby diffusion from the capillaries. Thus positioning the sensors againstthe palpebral conjunctiva during blinking can increase the delivery ofsubstrates to the contact device biosensor allowing a useful amount ofsubstrates to diffuse through the contact device biosensor membranes.

[0177] There are several locations on the surface of the eye in whichthe ICL can be used to measure glucose such as: the tear film laying onthe surface of the cornea which is an ultrafiltrate of blood derivedfrom the main lacrimal gland; the tear meniscus which is a reservoir oftears on the edge of the eye lid; the supero-temporal conjunctivalformix which allows direct measurement of tears at the origin ofsecretion; the limbal area which is a highly vascularized area betweencornea and the sclera; and preferably the highly vascularizedconjunctiva. The contact device allows the most efficient way ofacquiring fluid by creating micro-damage to the epithelium with aconsequent loss of the blood barrier function of said epithelium, withthe subsequent increase in tissue fluid diffusion. Furthermore,mechanical irritation caused by an intentionally constructed slightlyrugged surface of the contact device can be used in order to increasethe flow of substrates. Furthermore, it is understood that a heatingelement can be mounted in association with the sensor in order toincrease transudation of fluid.

[0178] The samples utilized for noninvasive blood analysis maypreferably be acquired by micro-traumas to the conjunctiva caused by thecontact device which has micro projections on its surface in contactwith the conjunctiva creating an increase in the diffusion rate ofplasma components through the capillary walls toward the measuringsensors. Moreover, the apparatus of the invention may promote increasedvascular permeability of conjunctival vessels through an increase intemperature using surface electrodes as heating elements. Furthermore,the sensors may be located next to the exit point of the lacrimal glandduct in order to collect tear fluid close to its origin. Furthermore,the sensors may be placed inferiorly in contact with the conjunctivaltear meniscus which has the largest volume of tear fluid on the surfaceof the eye. Alternatively, the sensors may be placed in contact with thelimbal area which is a substantially vascularized surface of the eye.Any means that create a micro-disruption of the integrity of the ocularsurface or any other means that cause transudation of tissue fluid andconsequently plasma may be used in the invention. Alternatively, thesensors may be placed against he vascularized conjunctiva in thecul-de-sac superiorly or inferiorly.

[0179] It is also understood that the sensors can be placed on anylocation on the surface of the eye to measure glucose and other chemicalcompounds. Besides the conventional circular shape of contact lenses,the shape of the contact device also includes a flat rectangularconfiguration, ring like or half moon like which are used forapplications that require placement under the palpebral conjunctiva orcul-de-sac of the eye.

[0180] A recessed region is created in the contact device for placementof the electrodes and electronics with enzyme active membranes placedover the electrodes. A variety of membranes with differentpermeabilities to different chemical species are fitted over theelectrodes and enzyme-active membranes. The different permeability ofthe membranes allows selection of different chemicals to be evaluatedand to prevent contaminants from reaching the electrodes. Thus allowingseveral electroactive compounds to be simultaneously evaluated bymounting membranes with different permeabilities with suitableelectrodes on the contact device.

[0181] It is also understood that multilayer membranes with preferentialpermeability to different compounds can be used. The contact deviceencases the microelectrodes forming a bioprotective membrane such thatthe electrodes are covered by the enzyme active membrane which iscovered by the contact device membrane such as polyurethane which isbiocompatable and permeable to the analytes. A membrane between theelectrodes and the enzyme membrane can be used to block interferingsubstances without altering transport of peroxide ion. The permeabilityof the membranes are used to optimize the concentration of the compoundsneeded for the enzymatic reaction and to protect against interferingelements.

[0182] It is understood that the diffusion of substrate to the sensormounted in the contact device is preferably perpendicular to the planeof the electrode surface. Alternatively, it is understood that themembrane and surface of the contact device can be constructed to allowselective non-perpendicular diffusion of the substrates. It is alsounderstood that membranes such as negatively charged perfluorinatedionomer Nafion membrane can be used in order to reduce interference byelectroactive compounds such as ascorbate, urate and acetaminophen. Itis also understood that new polymers and coatings under developmentwhich are capable of preferential selection of electroactive compoundsand that can prevent degradation of electrodes and enzymes can be usedin the apparatus of the invention.

[0183] The sensors and membranes coupled with radio transmitters can bepositioned in anyplace in the contact device but may be placed in thecardinal positions in a pie like configuration, with each sensortransmitting its signal to a receiver. For example, if four biologicalvariables are being detected simultaneously the four sensors signals A,B, C, and D are simultaneously transmitted to one or more receivers. Anydevice utilizing the tear fluid to non-invasively measure the bloodcomponents and signals transmitted to a remote station can be used inthe apparatus of the invention. Preferably a small contact device,however any size or shape of contact devices can be used to acquire thedata on the surface of the eye.

[0184] An infusion pump can be activated according to the level ofglucose detected by the ICL system and insulin injected automatically asneeded to normalize glucose levels as an artificial pancreas. An alarmcircuit can also be coupled with the pump and activated when low or highlevels of glucose are present thus alerting the patient. It isunderstood that other drugs, hormones, and chemicals can be detected andsignals transmitted in the same fashion using the apparatus of theinvention.

[0185] A passive transmitter carrying a resonance circuit can be mountedin the contact device with its frequency altered by a change inreactance whose magnitude changes in response to the voltage generatedby the glucose sensors. As the signal from passive transmitters fallsoff extremely rapidly with distance, the antenna and receiver should beplaced near to the contact device such as in the frame of regularglasses.

[0186] It is also understood that active transmitters with batterieshoused in the contact device and suitable sensors' as previouslydescribed can also be used to detect glucose levels. It is alsounderstood that a vibrating micro-quartz crystal connected to a coil andcapable of sending both sound and radio impulses can be mounted in thecontact device and continuously transmit data signals related to theconcentration of chemical compounds in the tear fluid.

[0187] An oxygen electrode consisting of a platinum cathode and a silveranode loaded with polarographic voltage can be used in association withthe glucose sensor with the radio transmission of the two variables. Itis also understood that sensors which measure oxygen consumption asindirect means of evaluating glucose levels can be used in the apparatusof the invention. The membranes can be used to increase the amount ofoxygen delivered to the membrane enzyme since all glucose oxidasesystems require oxygen and can potentially become oxygen limited. Themembranes also can be made impermeable to other electroactive speciessuch as acetamymophen or substances that can alter the level of hydrogenperoxide produced by the glucose oxidase enzyme membrane.

[0188] It is understood that a polarographic Clark-type oxygen detectorelectrode consisting of a platinum cathode in asilver-to-silver-chloride anode with signals telemetered to a remotestation can be used in the apparatus of the invention. It is alsounderstood that other gas sensors using galvanic configuration and thelike can be used with the apparatus of the invention. The oxygen sensoris preferably positioned so as to lodge against the palpebralconjunctiva. The oxygen diffusing across the electrode membrane isreduced at the cathode which produces a electrical current which isconverted to an audio frequency signal and transmitted to a remotestation. The placement of the sensor in the conjunctiva allows intimatecontact with an area vascularized by the same arterial circulation asthe brain which correlates with arterial oxygen and provides anindication of peripheral tissue oxygen. This embodiment allows goodcorrelation between arterial oxygen and cerebral blood flow bymonitoring a tissue bed vascularized by the internal carotid artery, andthus, reflects intracranial oxygenation.

[0189] This embodiment can be useful during surgical procedures such asin carotid endarterectomy allowing precise detection of the side withdecreased oxygenation. This same embodiment can be useful in a varietyof heart and brain operations as well as in retinopathy of prematuritywhich allows close observation of the level of oxygen administered andthus prevention of hyperoxia with its potentially blinding effects whilestill delivering adequate amount of oxygen to the infant.

[0190] Cholesterol secreted in the tear fluid correlates with plasmacholesterol and a further embodiment utilizes a similar system asdescribed by measurement of glucose. However, this ICL as designed bythe inventor involves an immobilized cholesterol esterase membrane whichsplits cholesterol esters into free cholesterol and fatty acids. Thefree cholesterol passes through selectively permeable membrane to bothfree cholesterol and oxygen and reaches a second membrane consisting ofan immobilized cholesterol oxidase. In the presence of oxygen the freecholesterol is transformed by the cholesterol oxidase into cholestenoneand hydrogen peroxide with the hydrogen peroxide being oxidized on thesurface of the working electrode which creates a measurable electriccurrent with signals preferably converted into audio frequency signalsand transmitted to a remote receiver with the current being proportionalto the cholesterol concentration according to calibration factors. Themethod and apparatus described above relates to the following reactionor part of the following reaction.

[0191] Cholesterol ester cholesterol esterase° Free cholesterol+fattyacids

[0192] Free cholesterol+O_(2 cholesterol oxidase)° Cholestenone+H₂O₂

[0193] A further embodiment utilizes an antimone electrode that can behoused in the contact device and used to detect the pH and otherchemical species of the tear fluid and the surface of the eye. It isalso understood that a glass electrode with a transistor circuit capableof measuring pH, pH endoradiosondes, and the like can be used andmounted in the contact device and used for measurement of the pH in thetear fluid or surface of the eye with signals preferably radiotransmitted to a remote station.

[0194] In another embodiment, catalytic antibodies immobilized in amembrane with associated pH sensitive electrodes can identify a varietyof antigens. The antigen when interacting with the catalytic antibodycan promote the formation of acetic acid with a consequent change in pHand current that is proportional to the concentration of the antigensaccording to calibration factors. In a further embodiment an immobilizedelectrocatalytic active enzyme and associated electrode promote, in thepresence of a substrate (meaning any biological variable), anelectrocatalytic reaction resulting in a current that is proportional tothe amount of said substrate. It is understood that a variety ofenzymatic and nonenzymatic detection systems can be used in theapparatus of the invention.

[0195] It is understood that any electrochemical sensor, thermoelectricsensors, acoustic sensors, piezoelectric sensors, optical sensors, andthe like can be mounted in the contact device and placed on the surfaceof the eye for detection and measurement of blood components andphysical parameters found in the eye with signals preferably transmittedto a remote station. It is understood that electrochemical sensors usingamperometric, potentiometric, conductometric, gravimetric, impedimetric,systems, and the like can be used in the apparatus of the invention fordetection and measurement of blood components and physical parametersfound in the eye with signals preferably transmitted to a remotestation.

[0196] Some preferable ways have been described; however, any otherminiature radio transmitters can be used and mounted in the contactdevice and any microminiature sensor that modulates a radio transmitterand send the signal to a nearby radio receiver can be used. Othermicrominiature devices capable of modulating an ultrasound device, orinfrared and laser emitters, and the like can be mounted in the contactdevice and used for signal detection and transmission to a remotestation. A variety of methods and techniques and devices for gaining andtransmitting information from the eye to a remote receiver can be usedin the apparatus of the invention.

[0197] It is an object of the present invention to provide an apparatusand method for the non-invasive measurement and evaluation of bloodcomponents.

[0198] It is also an object of the present invention to provide anintelligent contact lens system capable of receiving, processing, andtransmitting signals such as electromagnetic waves, radio waves,infrared and the like being preferably transmitted to a remote stationfor signal processing and analysis, with transensors and biossensorsmounted in the contact device.

[0199] It is a further object of the present invention to detectphysical changes that occur in the eye, preferably using opticalemitters and sensors.

[0200] It is a further object of the present invention to provide anovel drug delivery system for the treatment of eye and systemicdiseases.

[0201] The above and other objects and advantages will become morereadily apparent when reference is made to the following descriptiontaken in conjunction with the accompanying drawings.

[0202] The preferred way for evaluation of bodily functions such asdiagnostics and non-invasive blood analysis according to the presentinvention includes placing an intelligent contact lens on the A highlyvascularized conjunctiva@. By the present invention it has beendiscovered that the surface of the eye and surrounding tissues, inparticular the conjunctiva, is the ideal place for diagnostic studies,non-invasive blood analysis, and health status evaluation. This areaprovides all of the requirements needed for such diagnostics andevaluations including the presence of superficially located fenestratedblood vessels. This is the only area in the body which allows theundisturbed direct view of blood vessels in their natural state. Thepresent invention allows fluid and cell evaluation and diagnostics to benaturally done using the normal physiology of the eye and conjunctiva.

[0203] The fenestrated blood vessels in the conjunctiva aresuperficially located and leak plasma. Fenestrated blood vessels havepores and/or openings in the vessel wall allowing free flow of fluidthrough its vessel walls.

[0204] According to the principles of the invention, the surface of theeye and the conjunctiva and surrounding tissues provides the ideallocation in the human body for non-invasive analysis and other fluid andcellular diagnostics and the preferred way for evaluation of bodilyfunctions and non-invasive blood analysis. The conjunctiva is theextremely thin continuous membrane which covers the anterior portion ofthe eye and eye lid and ends in the limbus at the junction with thecornea and at the junction of the skin of the eye lid. The conjunctivais a thin transparent membrane that covers the Awhite@ of the eye as thebulbar conjunctiva and lines the eye lids as the palpebral conjunctiva.The conjunctiva has a vast network of blood vessels and lies on a secondnetwork of blood vessels on the episclera. The episcleral network ismuch less voluminous than the conjunctival vessel network.

[0205] The epithelium of the conjunctiva is a stratified columnarepithelium made up of only three or less layers of cells, and the middlelayer (polygonal cells) is absent in most of the palpebral conjunctiva.Physiologic, anatomic and in-vitro studies by the inventor demonstratedthat the blood vessels in the conjunctiva are fenestrated, meaning havepores, and leak plasma to the surface of the eye and that this plasmacan be evaluated when a device is placed in contact with theconjunctiva. The sensing device can be held by any part of the eye lids,partially when the device is not placed in the cul-de-sac or totallywhen the sensing device is placed in the conjunctival pocket under theeye lid (lower or upper cul-de-sac).

[0206] Unlike other tissues covering the body the conjunctiva has a vastnetwork of blood vessels which are superficially located and easilyaccessible. This can be seen by pulling down the lower eye lid andlooking at the red tissue with the actual blood vessels beingvisualized. Those blood vessels and thin membrane are protected by theeye lid and the palpebral conjunctiva is normally hidden behind the eyelids. The blood vessels are in close proximity to the surface and theredness in the tissue is due to the presence of the vast network ofsuperficial blood vessels. This area of the body allows the undisturbeddirect view of the blood vessels. Besides the fact that the bloodvessels have thin walls and are superficially located, those vesselshave a very important and peculiar feature—fenestration with continuousleakage of plasma to the surface of the eye. The plasma continuouslyleaks from the conjunctival blood vessels, and since they aresuperficially located, only a few micrometers have to be traveled bythis fluid to reach the surface of the eye, with the fluid being thenacquired by the diagnostic system of the intelligent contact lens of thepresent invention in apposition to the tissue surface.

[0207] Besides the presence of such superficial and fenestrated vessels,the conjunctiva, contrary to the skin, has a thin epithelium with nokeratin which makes acquisition of signals a much easier process.Moreover, the conjunctiva has little electrical resistance due to thelack of a significant lipid layer as found in the skin such as thestratum corneum with a good rate of permeation of substances.

[0208] It is important to note that the acquisition of the signal asdisclosed by the invention involves a natural occurrence in which theeye lid and surrounding ocular structures hold the sensing device indirect apposition to the conjunctiva. The simple apposition of theintelligent contact lens to the conjunctiva can create a stimuli forflow toward the sensor and the eye lid; muscular function works as anatural pump. Furthermore, the lack of keratin in the conjunctiva alsoeliminates a critical barrier creating the most suitable place forevaluation of bodily functions and non-invasive cell analysis withepithelial, white blood cells, and the like being naturally orartificially pumped into the intelligent contact lens for analysis.

[0209] The contact lens according to the principles of the presentinvention provides the ideal structure which is stable, continuous andcorrectly positioned against the tissue, in this case the Living thinsuperficial layer of the thin conjunctiva of the eye. The eye lidsprovide the only natural and superficial means in the body for sensorapposition to the tissues being evaluated without the need for othersupporting systems creating a perfect, continuous and undisturbednatural and physiologic contact between the sensing devices and tissuesdue to the natural anatomy and tension present in the cul-de-sac of theeye lids.

[0210] The natural pocket that is formed by the eye lids provides theideal location for the undisturbed placement of sensing devices such asthe intelligent contact lens of the present invention. Besides providingan undisturbed place for sensor placement and apposition, the naturaleye lid pocket provides a place that is out of sight allowing a moredesirable cosmetic appearance in which no hardware is exposed or visibleto another person.

[0211] The eye lids are completely internally covered by the conjunctivaallowing a vast double surface, both anterior and posterior surface, tobe used as an area to acquire signals for chemicals, protein and cellevaluation. Furthermore and of vital importance is the fact that the eyelid is also the only place in the body that work as a natural pump offluid to sensing devices.

[0212] The eye lid creates a natural pump effect with a force of 25,000dynes. The force generated by the eye lids is used by the presentinvention to move fluids and cells toward sensing devices and works asthe only natural enhancer to increase fluid transport and cell motiontoward a sensing device. The pumping and/or tension effect by the eyelid allows the fluid or cells to more rapidly reach and permeate thesensor surface.

[0213] The presence of the intelligent contact lens against theconjunctiva in the conjunctival pocket creates physiologic changes whichincreases flow and permeation of fluid flux towards the sensor. The lenscan be made irregular which creates friction against the thin andloosely arranged cell layers of the conjunctiva providing a furtherincrease of flow of fluid and cells to the sensor. Since the bloodvessels in the conjunctiva are fenestrated and superficial the fluidflows freely from the vessels to the surface. This rate of flow can beenhanced by the presence of the lens and the friction that is createdbetween lens surface and conjunctiva due to the tension and muscularactivity present in the eye lid. The free flow of fluid associated withthe natural pump action of the eye lid moves fluid toward theintelligent contact lens which can be used to store such fluid and cellsfor immediate or later processing.

[0214] When the later processing method is used, the partial or completeintelligent contact lens is removed from the eye for further evaluation.A variety of ionization storage areas can be housed in the intelligentcontact lens with the flow of fluid being continuously carried out bythe eye lid pumping action. Furthermore, the conjunctiva provides alarge area for housing the diagnostic systems of the intelligent contactlens with its microchips, microsensors, and hardware for signalacquisition, evaluation, processing and transmission. There is asurprising amount of space in the conjunctiva and its natural pocketsunder the eye lid in each eye. An average of 16 square centimeters ofconjunctival area in the human eye allows enough area for housing thenecessary lens hardware including two natural large pocket formationsunder the lower and upper eye lid. Since the superficial layer of theconjunctiva is a living tissue, contrary to the skin which is deadtissue, a variety of materials can be used in the lens to create theapposition needed by combining hydrophilic and hydrophobic biocompatiblematerial lens surfaces such as hydroxyethylmethacrylate and siliconewhich allow precise balance of material to create the apposition andisolation from contaminants while even creating a suction cup effect toincrease fluid flow.

[0215] An exemplary housing of the intelligent contact lens can consistof a surrounding silicone surface which creates adherence around thesensor surface and thus prevents contaminants to reach the sensor. Thefluid or cells to be evaluated are then kept isolated from the remainingenvironment of the eye and any potential contaminant. The remainingportion of the contact lens can be made with hydrogel such ashydroxyethylmethacrylate which is physiologic for the eye. It isunderstood that a variety of lens materials presently used for or laterdeveloped for contact lenses can be used as housing material. Any othernew materials used in conventional contact lenses or intraocular lensescan be used as the housing for the diagnostic systems of the intelligentcontact lens of the present invention. Moreover since the diagnosticintelligent contact lens is preferably placed in the cul-de-sac orconjunctival pocket, there is no problem with oxygen transmissibilityand corneal swelling as occurs with contact lenses placed on the cornea.

[0216] Contact lenses placed on the cornea generally cause hypoxicstress leading to corneal swelling when said contact lenses are worn forextended periods of time. The conjunctiva is highly vascularized withinternal supply of oxygen allowing extended wear of the contact lensesplaced in the conjunctival pocket. Contrary to that, the cornea isavascular and requires external supply of oxygen to meet its metabolicneeds.

[0217] The high oxygen content present in the conjunctiva is also anadvantage for amperometric sensing systems in which oxygen is used as asubstrate. Oxygen is present in lower concentrations in the skincreating an important limiting factor when using amperometric systemsplaced on or under the skin. Similar to the skin, mucosal areas in thebody such as oral or gastrointestinal, ear, and nasal passages sufferfrom equivalent drawbacks and limitations.

[0218] Therefore, preferably, by utilizing a natural physiologic actionin which there is continuous free flow of fluid through blood vesselsassociated with the continuous tension effect by the lid and a thinpermeable tissue layer such as the conjunctival epithelium, the systemof the invention is capable of providing continuous measurement offluids allowing the creation of a continuous feedback system. Theintelligent contact lens as described can have magnetic and/or electricelements which are actuated by electrical force or external magneticforces in order to enhance the performance and/or augment the functionsof the system. The dimensions and design for the lens are made in orderto optimize function, comfort, and cosmesis. For example, a length ofless than 4 mm and a height of less than 7 mm for the lower pocket andless than 10 mm for the upper pocket may be used. A thickness of lessthan 2.5 mm, and preferably less than 1.0 mm, would be used. Thediagnostic systems of the intelligent contact lens of the presentinvention is referred to herein as any AICL@ which is primarily used forfluid, chemicals, proteins, molecular or cell diagnosis and the like.

[0219] The epithelium of the conjunctiva is very thin and easilyaccessible both manually and surgically. The layers of the conjunctivaare loosely adherent to the eyeball allowing easy implantation ofsensing devices underneath said conjunctiva. The intelligent implant ofthe present invention is an alternative embodiment to be used inpatients who want continuous measurement of blood components withouthaving to place an ICL on the surface of the conjunctiva. The surgicalimplantation can be done in the most simple way with a drop of localanesthetic followed by a small incision in the conjunctiva withsubsequent placement of the sensing device. The sensing device with itshardware for sensing and transmission of signals is implanted underneaththe conjunctiva or in the surface of the eye and is continuously bathedby the plasma fluid coming from the fenestrated conjunctival bloodvessels. Although, a conventional power source can be housed in the ICL,the implanted ICL can be powered by biological sources with energy beingacquired from the muscular contraction of the eye muscles. The eyemuscles are very active metabolically and can continuously generateenergy by electromechanical means. In this embodiment the eye lid muscleand/or extraocular muscle which lies underneath the conjunctiva isconnected to a power transducer housed in the ICL which converts themuscular work into electrical energy which can be subsequently stored ina standard energy storage medium.

[0220] Besides the exemplary electromechanical energy source, otherpower sources that are suitable for both implanted and externally placedICLs would include lightweight thin plastic batteries. These batteriesuse a combination of plastics such as fluorophenylthiophenes aselectrodes and are flexible allowing better conformation with theanatomy of the eye.

[0221] Another exemplary suitable power source includes a light weightultra-thin solid state lithium battery comprised of a semisolid plasticelectrolyte which are about 150 μm thick and well suited for use in theICL. The power supply can also be inactive in order to preserve energywith a switch triggered by muscle action whenever measurement is neededaccording to patient=s individual condition.

[0222] The implanted ICL provides continuous measurement of analytescreating a continuous feedback system. A long-term implanted ICL can beused without the need for replacement of reagents. As an alternativeimplanted ICLs can use enzymatic systems that require replacement ofenzymes and when such alternative embodiment is used the whole implantedICL can be removed or simply a cartridge can be exchanged or enzymaticmaterial inserted through the ICL housing into its appropriate place.All of this manipulation for implanted ICLs can be easily done with asimple drop of anesthetic since the conjunctival area is easilyaccessible. Contrary to the skin which is non-transparent, theconjunctiva is transparent allowing easy visualization of the implantedICL. Contrary to other parts of the body the procedure can be done in avirtually bloodless manner for both insertion, removal and replacementif needed.

[0223] It is important to note that previously, after removing bloodfrom a patient, major laboratory analysis was required consisting of theseparation of blood components to acquire plasma. In the case of theconjunctiva and the eye, according to the principles of the invention,the body itself deliver the plasma already separated for measurement andfreely flowing to the ICL sensing device externally or internally(surgically) placed. To further create the perfect location forevaluation of bodily functions, the conjunctival area is poorlyinnervated which allows placement of the ICL in the conjunctival sac forlong periods of time with no sensation of discomfort by the user. Thereare only few pain fibers, but no pressure fibers in the conjunctiva.Furthermore, as mentioned, there is a vast amount of space under thelids allowing multiple sensing devices and other hardware to be placedin the conjunctival area.

[0224] To further provide the perfect location for measurements of fluidand cells, the sensing device can be held in place by the eye lidcreating the perfect apposition between the surface of the eye and theICL sensor. Since the blood vessels are superficially located, only afew micrometers have to be traveled by the fluid to reach the surface ofthe eye, with the fluid being then acquired by the ICL in apposition tothe tissue surface. No other organ has the advantage of the naturalpocket of the eye lid to secure a sensor in position and appositionnaturally without need of other devices or external forces. Acombination of a hydrophobic and a hydrophilic surface of the ICLhousing creates the stability that is needed for the ICL to remain inany type of apposition to the conjunctival surface, meaning more tightlyadherent or less adherent to the conjunctival surface according to theevaluation being carried out. To further create the prefect environmentfor evaluation of blood components, the eye lid during blinking orclosure, creates a pump effect which is an adjunctive in directing theplasma components toward the sensor.

[0225] The present invention uses plasma, but non-invasively.Furthermore, contrary to the finger, the ocular surface evaluated by thesystem of the present invention is irrigated by a direct branch from thecarotid artery allowing the direct evaluation of brain analyte level.The brain analyte level is the most important value for the evaluationof the metabolic state of a patient.

[0226] The cells of the epithelium of the conjunctiva are alive andloosely adherent allowing cell analysis to be performed using the ICL,contrary to the skin surface which is dead. The ICL can naturally removethe cells from the surface during the action of the eye lid or bymechanical pumping means or electrical means and then living cells canthen be extracted for further evaluation within the ICL or outside theICL. Appropriate membrane surfaces are used to separate cells componentsand fluid components. Different permeabilities of membranes inapposition to the conjunctiva are used according to the function that iscarried out or the function of a particular ICL.

[0227] The present invention brings not only innovation but also acost-effective system allowing diagnostic and blood evaluation to bedone in a way never possible before. The current invention allowsunbelievable savings for the patient, government and society in general.An ICL can be disposable and provide continuous measurement over 24hours and costs to the user around $5 to $8 dollars for one single ormultiple testing ICL (meaning more than one analyte is evaluated). Thematerial used in the ICL includes an inexpensive polymer. The reagentsand/or enzymatic membranes are used in very small quantities and arealso thus inexpensive, and the electronics, integrated circuits andtransmitter are common and fairly inexpensive when mass produced as isdone with conventional chips.

[0228] The current invention provides means to better control healthcare expenditure by delivering systems that are astonishingly 20 timescheaper than the prior art using a variety of means ranging fromlow-cost amperometric systems to disposable microfluidic chips andintegration of biochemical and disposable silicon chip technologies intothe ICLs. The ICLs can perform numerous analysis per lens and if justone more test is performed the cost of ICL remains about the same sincethe new reagents are used in minute quantities and the similarelectronics can be used in the same ICL. In this case, with dual testing(two tests per lens, four times a day) the ICL is a staggering 100 timescheaper.

[0229] The system of the invention allows a life-saving technologicalinnovation to help contain health care costs and thus enhance theoverall economy of the nation, as well as to not only provide atechnological innovation that can be used in industrialized nations butalso in economically challenged countries, ultimately allowinglife-saving diagnostic and monitoring biological data to be accessiblein a cost-effective and wide-spread manner. Moreover, this affordablesystem allows not only individual measurements but also continuous 24hour non-invasive measurement of analytes including during sleeping,allowing thus the creation of an artificial organ with preciselytailored delivery of medications according to the analyte levels.

[0230] Although the ICL externally placed is the preferred way, asurgical implant for continuous monitoring is a suitable alternativeembodiment as described above. Furthermore, it is understood that asmall rod with sensing devices housed in the tip can be used. In thatembodiment the patient places the sensor against the conjunctiva afterpulling the eye lid down and exposing the red part and then applying thesensing device against it for measurement. Alternatively, the tip of therod is lightly rubbed against the conjunctiva to create microdisruptionas naturally caused by the eyelid tension, and then the sensing deviceis applied and the sensor activated for measurement. It is understoodthat any other means to promote or increase transudation of plasma inthe conjunctiva can be used with the ICL, including, but not limited toheating systems, creating a reverse electroosmotic flow,electrophoresis, application of current, ultrasonic waves as well aschemical enhancers of flow, electroporation and other means to increasepermeation.

[0231] An exemplary embodiment of the diagnostic ICLs provides acontinuous measurement of the analyte by means of biosensing technology.These ICL biosensors are compact analytical devices combining abiological sensing element coupled with a physicochemical transducerwhich produces a continuous or discrete electronic signal that isproportional to the concentration of the elements or group of elementsbeing evaluated. The diagnostic ICLs then can continuously measure thepresence or the absence of organic and inorganic elements in a rapid,accurate, compact and low-cost manner. A variety of biosensors can beused as previously described including amperometric with otherconventional parts as high impedance amplifiers with associated powersupply as well as potentiometric, conductometric, impedimetric, optical,immunosensors, piezoimmunobiosensor, other physicocehmical biosensorsand the like.

[0232] Some of the amperometric systems described produce a currentgenerated when electrons are exchanged between a biological system andan electrode as the non-invasive glucose measuring system referred toherein as AGlucoLens@. The potentiometric ICLs measure the accumulationof charge density at the surface of an electrode as in ion-selectivefield-effect transistors (ISFET) such as for measuring sodium,potassium, ionized calcium, chloride, gases as carbon dioxide, pH, andthe like present in the eye.

[0233] Optical diagnostic biosensors ICL correlates the changes in themass or concentration of the element with changes in the characteristicof the light. It is also understood that the diagnostic ICLs can utilizeother forms for biosensing such as changes in ionic conductance,enthalpy, mass as well as immunobiointeractions and the like.

[0234] The miniaturization and integration of biochemical/chemicalsystems and microelectronic technologies can provide the microscopicanalytical systems with integrated biochemical processing that arehoused in the ICLs for fluid and cell evaluation. ICLs can then performall of the steps used in a conventional laboratory using minute amountsof reagents being capable of evaluating any blood, plasma or tissuecomponents. Advances in nanotechnology, micro and nanoscale fabrication,nanoelectronics, A smart dust@ and the like will create systems ofinfinitely small dimensions which can be used in ICLs allowing multiplefluid and cell evaluation to be done simultaneously in one single ICL.Therefore, thicknesses of less than 0.5 mm for the ICL are likely.

[0235] Another exemplary-embodiment of the diagnostic ICLs providechemical, genetic, and other analytical evaluations usingmicrofabricated bioelectronic chips with the acquisition of biochemicaland chemical information using microsystems with microfabrication ofchemical integrated circuits and other silicon chip biochemicaltechnologies. ICLs can house a variety of microscopic means for fluidand cell handling and biochemical processing devices. Diagnostic ICLsprovide a complete analysis of the fluid and cells being acquired fromthe eye with elements being transported into the ICL for analysisaccording to the principles of the invention.

[0236] In this embodiment the ICL comprises a microchip usingmicrofluidics and chemical/biochemical microchip technology creating acomplete chemical processing system. Using electrical impulses the ICLscan actively direct small quantities of fluid to different parts of theICL structure in fractions of a second for further analysis in acompletely automated way with the detectable signal result beingpreferably radiotransmitted to a remote station according to theprinciples of the invention.

[0237] The ICL biomicrochips can be produced using photolithography,chemical etching techniques and silicon chip technologies similar tothose used in the manufacture of computer chips. The ICL system thusachieve the miniaturization needed for the ICL dimensions withmicrochannels etched into the chip substrate measuring up to 100micrometers, and preferably up to 10 micrometers in depth, by 1 to 500micrometers, and preferably 10 to 100 micrometers wide.

[0238] The microchannels carry the fluid and cells from the eye and havereservoirs and chambers with the reagents and sample solutions neededfor analysis. The ICL radio frequency transceivers comprisemicroelectronic systems with radio frequency integrated circuitsallowing the small dimensions to be achieved for incorporation into theICL.

[0239] A variety of power sources have been described, but in order tominimize hardware and cost of the ICL, an ultra-capacitor chargedexternally through electromagnetic induction coupling can be usedinstead of the polymer microbatteries or rechargeable batteries.Although there is an enormous amount of space in the conjunctival area,with two large pockets in each eye as described, allowing much largersystems to be used, it is preferable that the most miniaturized systembe used which then allows multiple tests to be simultaneously performed.

[0240] The exemplary ICL embodiments contain on a microscopic scaleequivalent elements to all of the elements found in conventionallaboratories such as pumps, valves, beakers, separation equipment, andextractors, allowing virtually any chemical preparation, manipulationand detection of analytes to be performed in the ICLs. The pumps,reactors, electrical valves, filters, sample preparation can be createdpreferably by the application of electrical charges and piezoelectriccharges to the channels and structure of the ICL allowing directing offluid to any part of the ICL structure as needed, coupled to theanalysis of the material with the completion of numerous biochemical,cell-based assays, and nucleic acid assays. Current and future advancesin microfluidics, electrically conducting liquids, microcapillaryelectrophoresis, electrospray technology, nanofluidics, ultrafineparticles, and nanoscale fabrication allows the creation of severalanalytical system within one single ICL with the concomitant analysis ofcancer markers, heart markers, DNA mutations, glucose level, detectionof infectious agents such as bacteria, virus, and the like using samplesfrom the eye in the microliter and picoliter scales.

[0241] Diagnostic ICLs can perform molecular separations using numeroustechniques. Complete clinical chemistry, biochemical analysis, nucleicacid separation, immunoassays, and cellular processing, can be performedon a continuous manner by using the appropriate integration of chip withbiochemical processing and associated remote transmission associatedwith the continuous flow of fluid and cells from the eye. ICLs containnumerous elements for a variety of microfluidic manipulation andseparation of plasma or fluid components acquired from the surface ofthe eye for chemical analysis. Since there is a continuous flow of fluidfrom the conjunctival surface to the sensing devices and systems in theICL, the sensing devices and systems can perform continuous biochemicalevaluation while moving minute amounts of fluid through the microscopicchannels present in a microchip contained in the structure of the ICL.

[0242] A variety of chemical microchips can be used creating motion offluid through microchannels using electrokinetic forces generated withinthe structure of the ICL. Microwires, power sources, electrical circuitsand controllers with the associated electronics generate certain changesin electrical voltage across portions of the microchip which controlsthe flow rate and direction of the fluid in the various channels andparts of the microchip housed in the structure of the ICL creating anautomated handling of fluids within the ICL and a complete chemicalprocessing systems within the ICL, preferably without any moving partswithin the ICL structure. However, micropumps, microvalves, othermicroelectrical and mechanical systems (MEMS) and the like can be usedin the present invention.

[0243] The ICLs provide a cost-effective system which can be broadly androutinely used for a range of classical screening applications,functional cell-based assays, enzyme assays, immunoassays, clinicalchemistry such as testing for glucose, electrolytes, enzymes, proteins,and lipids; as well as toxicology and the like in both civilian andmilitary environments. A critical element in the battlefield in thefuture will be the detection of biological or chemical weapons. One ofthe ways to detect the use of weapons by enemy forces unfortunatelyrelies on detection of immediate illness and most often, later afterillness is spreading, since some of the damaging effects do not elicitimmediate symptoms and cause serious damage until time goes on. Troopscan use an ICL with detection systems for the most commonchemical/biological weapons. The ICLs create a 24 hour surveillancesystem identifying any insulting element, even in minute amounts,allowing proper actions and preventive measures to be taken beforeirreversible or more serious damage occur.

[0244] A dual system ICL with tracking and chemical sensing can be animportant embodiment in the battlefield as troops exposed to chemicalweapons are not only identified as exposed to chemical weapons but alsoimmediately located. In this exemplary embodiment the ICL position canbe located using for instance Global Positioning System (GPS), fixedfrequency, or the like. The GPS is a sophisticated satellite-basedpositioning system initially built in the mid-1970s by the United StatesDepartment of Defense to be used primarily in military operations toindicate the position of a receiver on the ground. Radio pulses asspheres of position from the satellites in orbit intersect with thesurface of the earth marking the transceiver exact position. ICLtransceivers for instance in one eye determines position and a chemicalsensing ICL in the other eye determines a chemical compound. Besidesbeing placed externally in the eye, during military use, the ICL, bothtracking and chemical sensing, can be easily and temporarily surgicallyimplanted in the conjunctival pocket.

[0245] A surveillance system can be used in the civilian environment asfor instance detecting the presence of tumor markers, cardiac markers,infectious agents and the like. Very frequently the body providesinformation in the form of markers before some serious illnesses occurbut unfortunately those markers are not identified on a timely fashion.It is known that certain tumors release markers and chemicals beforegoing out of control and creating generalized damage and spread. Ifpatients could have access to those blood tests on a timely fashion,many cancers could be eliminated before causing irreversible andwidespread damage.

[0246] For example patients at risk for certain cancers can use the ICLon a routine basis for the detection of markers related to the cancers.The markers that appear when the cancer is spreading or becoming out ofcontrol by the body immune system can then be detected.

[0247] The same applies to a variety of disorders including heartattacks. Thus, if a patient has a family history of heart disease, hashigh cholesterol or high blood pressure, the patient uses the ICL forcardiac markers on a periodic basis in order to detect the presence ofmarkers before a potentially fatal event, such as a heart attack,occurs.

[0248] A temperature sensing ICL, as previously described, can becoupled with an infection detecting system in patients at risk forinfection such as post-transplant recovery or undergoing chemotherapy.The temperature sensing ICL continuously monitors the temperature and assoon as a temperature spike occurs it activates the cell sensing ICL todetect the presence of infectious agents. The conjunctival surface is anideal place for continuous temperature measurement by allowingmeasurement of core temperature without the need to use a somehowinvasive and/or uncomfortable means.

[0249] As micro and nanofabrication evolves, a variety of analytes andphysical changes, such as for instance temperature changes, can beevaluated with one single ICL with fluid and tissue specimens beingdirected to parallel systems allowing multiple assays and chemicalanalysis to be performed in one individual ICL. By using both eyes andthe upper and lower eye lid pockets of each eye a large of number oftesting and monitoring means can be achieved at the same time by eachpatient, ultimately replacing entire conventional laboratories whileproviding life-saving information.

[0250] While sleeping chemical and physical signs can be identified withthe ICL which can remain in place in the eye in intimate contact withnot only the body, chemically and physically, but also in direct contactwith the two main vital organs, the brain and the heart. A single ICL ora combination of an ICL to detect physical changes and a chemical ICLcan detect markers related to sudden death and/or changes in blood gas,brain and heart activity, and the like. If timely identified many ofthose situations related to unexplained death or sudden death can betreated and lives preserved.

[0251] The type of ICL can be tailored to the individual needs of apatient, for instance a patient with heart disease or family history ofheart disease or sudden death can use an ICL for detection of elementsrelated to the heart. Since the ICLs are primarily designed to be placedon the conjunctiva in the eye lid pocket, there is virtually no risk forthe eye or decreased oxygenation in the cornea due to sleeping with alens. Thus, another advantage of the present invention is to providephysical and chemical analysis while the user is sleeping.

[0252] Another combination of ICLs systems concerns the ICL whichidentifies the transition between sleep and arousal states. It isimpossible for human beings to know the exact time one falls asleep. Onemay know what time one went to bed, but the moment of falling asleep isnot part of the conscious mind. The reticular formation in the braincontrols the arousal state. Interestingly, that brain function isconnected with an eye function, the Bell phenomena. An alarm system toprevent the user from falling asleep (referred herein as Alert ICL), forexample while driving or operating machinery may be used. In anotherexemplary embodiment, the Alert ICL is coupled to a Therapeutic ICL torelease minute amounts of a drug that keeps the patient alert andoriented.

[0253] The fluid in the tissue or surface of the eye is continuouslyloaded into the ICL chip preferably associated with the pump action ofthe eye lid but alternatively by diffusion or electrokinetically atpreset periods of time such as every 30 minutes in order to preservereagents present in the ICL microchip. A selective permeable membraneand/or a one-way microvalve can separate the compounds before they areloaded into the microchannels in the ICL chip. Plasma and other fluidsand cells can be electrically directed from the ocular tissue to the ICLsensing system and using electrical charges present or artificiallycreated in the molecules or by electromagnetic means multiple orindividual compounds can be directed to the ICL. The fluid and/or cellwith its individual substances reaches and selectively permeates the ICLsurface for analysis allowing specific compounds to be acquiredaccording to the ICL analytical system and reagents present. One of theprinciples related to the movement of fluid through the microchannels isbased on capillary electrophoresis.

[0254] The eye fluid for analysis flow through microscopic channelshoused in the ICL with the direction of flow being controlled byelectrical or electromagnetic means with changes in the configuration ofelectrical fields dynamically moving substances to a particulardirection and the voltage gradient determining the concentration andlocation of the substance along the channels. In an exemplary embodimentmicroelectrophoresis is used for chemical analysis with separation ofthe molecules according to their electrical charge and mass as well assimple diffusion with the consequent motion and separation of thesubstances for analysis.

[0255] Besides performing complete chemical processing and analysis, thesystem of the invention uses DNA or genetic chips in the micro andnanoarray dimensions and microfabricated capillary electrophoresis chipsto diagnose genetically based diseases using the fluid and cells flowingto the ICL present in the conjunctival pocket. The ICL provides acost-effective and innovative way to do screening and monitor therapy.DNA-chip systems in the ICL can perform all the processing and analysisof fluids preferably using capillary electrophoresis. A variety ofknown. DNA chips and other emerging technology in DNA chips can be usedin the ICL including, but not limited to, sequencing chips, expressionchips, and the like. PCR (polymerase chain reaction) can be done muchmore rapidly on a micro scale as with the ICL design.

[0256] The ICL microchip can have an array of DNA probes and useelectrical fields to move and concentrate the sample DNA to specificsites on the ICL microchip. These genetic ICLs can be used fordiagnosing diseases linked to particular genetic expressions or aberrantgenetic expressions using cells and/or fluid acquired by the ICLaccording to the principles of the invention.

[0257] For instance, the gene p450 and its eight different expressions,or mutations have been associated with a variety of cancers. Numerousoncogenes and tumor-suppressor genes can be detected by using the priorart with the conventional removal of blood, although the yield is verylow because of the limitation of sample collected at only one point intime. It is very difficult to find a tumor cell, chemical change ormarker among millions of cells or chemical compounds present in oneblood sample acquired at one point in time. The prior art collects oneblood sample and analyzes the sample in an attempt to find markers orother chemical and cell changes. As one can see it is by chance that onecan actually find a marker. Thus even after removing blood, sending itto the laboratory and analyzing the sample the result of this expensiveprocedure may be negative regardless of the fact of the patient actuallyhas the occult cancer or risk for a heart attack. These false negativesoccur because the sample is acquired in one point in time. Furthermoreeven if several blood samples are acquired over several hours which ispractically impossible and painful, the prior art has to detectcompounds and cells at very low concentrations and would have thus toperform several analysis isolating small samples to try to increase theyield.

[0258] With the system of the present invention there is continuous flowof analytes, cell and fluid to the ICL chips with the ICLs working on acontinuous mode to search for the marker 24 hours a day. The fluid iscontinuously acquired, processed within the ICL with subsequentreabsorption of the fluid and cells by the surface of the eye.

[0259] Please note that because the surface of the eye is composed ofliving tissue, contrary to the skin in which the keratin that coverssaid skin is dead, a completely recycled system can be created. Thefluid and cells move to the ICL and are analyzed in microamounts as theypass through the microchannels, network of channels, and detectionsystems, and if for instance a marker is found, the signal is wirelesslytransmitted to a remote receiver. The fluid then continues its movementtoward the place for reabsorption according to its diffusing propertiesor moved by electrokinetic forces applied within the structure andchannels of the ICL chip. In this manner, large amounts of sample fluid(although still nanoliters going through the microchannels) can be veryprecisely and finely analyzed as an ultrafiltrate going through a finesieve. The fluid flows through the chip with the chip continuouslycapturing fluid and cells for a variety of chemical analysis includinggenetic analysis since the continuous flow allows concentrating nucleicacid for analysis as it passes, for example, through the array structurein the chip.

[0260] Although selectively permeable membranes can be used to retainany toxic reagent, and those reagents are used in the picoliter andnanoliter range, alternatively, a disposal chamber can be used with thefluid and cells remaining in the ICL until being removed from the eye,for instance after 24 to 48 hours. In the case of a very complex DNAanalysis still not available in the ICL, the ICL can be alternativelytransferred to conventional macro equipment after the eye fluid isacquired, but preferably the complete analysis is done within the ICLwith signals transmitted to a remote station.

[0261] A variety of matrix and membranes with different permeabilitiesand pore sizes are used in the channels in order to size and separatecells and pieces of DNA. The continuous analysis provided by the systemprovides a reliable way for the detection of oncogenes and tumorsuppressing genes establishing a correlation betweenmeasurable-molecular changes and critical clinical findings such ascancer progression and response to therapy allowing a painless andbloodless surveillance system to be created. As the Human Genome Projectfurther identify markers and genes, the system of the invention canprovide a noninvasive, inexpensive, widespread analysis and detectionsystem by comfortably using a cosmetically acceptable device beinghidden under the eye lids or placed on the surface of the eye, butpreferably placed in any of the pockets naturally formed by the anatomyof the eye lids.

[0262] The control of electrical signals applied within the structure ofthe ICLs are microprocessor-based allowing an enormous amount ofcombinations of fluid and cell motion to be achieved and the finestcontrol of fluid motion within precise and specific time frames such asmoving positive charges to a certain microchannel and waiting a certainamount of time until reaction and processing occurs, and thenredirecting the remaining fluid for further processing at anotherlocation within the ICL, then mixing reagents and waiting a fixed amountof time until a new electrical signal is applied, in the same manner aswith semiconductor chips. The processing then is followed by separationof the products of the reaction and/or generation of a detectablesignal, and then further electrical energy is applied redirecting theremaining fluid to a disposal reservoir or to be reabsorbed by theocular surface. The cycle repeats again and as fluid is reabsorbed orleaves the system, more fluid on the other end is moved toward the ICLaccording to the principles described.

[0263] The ICLs accomplish these repetitive functions and analysisquickly and inexpensively using the charged or ionic characteristics offluid, cells and substances with electrodes applying a certain voltageto move cells and fluids through the ICL microchannels and reservoirs.The ICLs can be designed according to the type of assay performed withelectrical signals being modified according to the function and analysisdesired as controlled by the microprocessor including the timing of thereactions, sample preparation and the like. An ICL can be designed withcertain sensor and reagent systems such as for instance amperometric,optical, immunologic, and the like depending on the compound beinganalyzed. The only limiting factor is consumption of reagents which canbe replaced, or a cartridge-based format used, or preferably as adisposable unit. Since the ICL is low-cost and is easily accessiblemanually simply by pulling down the eyelid, the complete ICL can work asa disposable unit and be replaced as needed.

[0264] The design of the ICL is done in a way to optimize fluid flow andliquid-surface interaction and the channels can be createdphotolithographically in either silicon, glass, or plastic substratesand the like as well as combining chip technology and microbiosensorswith microelectronics and mechanical systems. Each ICL is preloaded withreagents, antigens, antibodies, buffer, and the like according to theanalysis to be performed and each reservoir on an ICL chip can be asource of enzymatic membranes, buffers, enzymes, ligand inhibitors,antigens, antibodies, substrates, DNA inhibitor, and the like. Themovement of fluids in the ICL can be accomplished mechanically as withthe lid pumping action, non-mechanically, electrically or as acombination.

[0265] The microstructures incorporated in the ICLs can efficientlycapture and move fluids and/or cells using the physiological pump actionof the eye lids and/or by using electrical charges to move and directspecific compounds toward specific sensors or detection units usingnanoliter volume of the biological sample and taking these minute samplevolumes and then moving them through the various stages of samplepreparation, detection, and analysis. The ICL system moves a measuredand precise volume of fluid according to the time that the voltage isapplied to the channels and the size of the channels. In the ICLmicrofluidics chips the fluid motion is primarily derived fromelectrokinetic forces as a result of voltages that are applied tospecific parts of the chip.

[0266] A combination of electroosmosis and electrophoresis moves bulkamounts of fluid along the channels according to the application of anelectrical field along the channel while molecules are moved to aparticular microelectrode depending on the charge of the molecule or/andaccording to its transport and diffusion properties. In electrophoresisthe application of voltage gradient causes the ions present in the eyefluid to migrate toward an oppositely charged electrode.

[0267] Electroosmosis relates to the surface charge on the walls of themicrochannels with a negative wall attracting positive ions. Then whenvoltage is applied across the microchannel the cations migrate in thedirection of the cathode resulting in a net flow of the fluid in thedirection of the negative electrode with a-uniform flow velocity acrossthe entire channel diameter. By applying voltages to various channelintersections, the ICL chip moves the eye fluid through the system ofmicrochannels and/or micro array systems, adjusting its concentration,diluting, mixing it with buffers, fragmenting cells by electricaldischarge, separating out the constituents, adding fluorescent tags anddirecting the sample past detection devices. The eye fluid can then,after processing, be moved to the detection units within the ICL.Numerous sensing devices and techniques can be used as part of theanalysis/detection system with creation of an optically detectable orencoded substance, chromatographic techniques, electrochemical, reactionwith antibodies placed within the structure of the ICL with thesubsequent creation of an end signal such as electrical current, changein voltage, and the like, with the signal wirelessly transmitted to aremote receiver. The current invention allows all of the steps to beperformed for data generation including acquisition, processing,transmission and analysis of the signal with one device, the ICL.

[0268] A variety of processes and apparatus can be used formanufacturing ICLs including casting, molding, spin-cast, lathing andthe like. An exemplary embodiment for low-cost mass production of theICL consists of production of the detection and transmission hardware(chemical microchips, processor, transmitter, power supply) as one unit(sheet-like) for instance mounted in polyamide or other suitablematerial. The sheet then, which can have different shapes, butpreferably a rectangular or ring-like configuration, is placed inside acavity defined between moulding surfaces of conventional contact lensmanufacturing apparatus. The moulding surfaces and cavity determine theshape and thickness of the ICL to be produced according to the functionneeded.

[0269] However, an ICL placed in an eye lid pocket or an annular ringcontact lens will have a maximum thickness of 2.5 mm, preferably lessthan 1.0 mm. An oversized round or regular round contact lensconfiguration having a diameter of less than 3 cm for an oversizecontact lens and a diameter less than 12 mm for a regular contact lens,will have a maximum thickness of 1.0 mm, and preferably less than 0.5mm.

[0270] After the hardware above is in the cavity, the lens polymer isdispensed into the cavity with subsequent polymerization of the lensmaterial as for instance with the use of heat, ultra-violet light, or byusing two materials which in contact trigger polymerization.Accordingly, the ICLs can be manufactured in very large quantities andinexpensively using moulding techniques in which no machining isnecessary. Although one exemplary preferred embodiment is described itis understood that a variety of manufacturing means and processes formanufacturing of lenses can be used and other materials such as alreadypolymerized plastic, thermoplastic, silicone, and the like can be used.

[0271] The ICL diagnostic system of the exemplary embodiment abovedescribed consists of an integration of chemical chips, microprocessors,transmitters, chemical sensing, tracking, temperature and otherdetecting devices incorporated within the structure of the contactdevice placed in the eye. Although the system preferably uses tissuefluid and cells, and plasma for analysis, it is understood that thereare certain markers, cells or chemical compounds present in the actualtear film that can be analyzed in the same fashion using a contact lensbased system.

[0272] The present invention allows the user to perform life-savingtesting while doing their daily routines: one can have an ICL in the eyedetecting an occult breast cancer marker while driving, or diagnosingthe presence of an infectious agent or mutation of a viral gene whiledoing groceries (if the mutation is detected in the patient, it can betreated on a timely fashion with the appropriate drug), while workinghaving routine clinical chemistry done, or while eating in a restaurantdetecting a marker for prostate cancer in one eye and a marker for heartattack in the other eye before heart damage and sudden death occurs, orone can have an ICL placed in the eye detecting genetic markers whilechecking their GPI e-mail with a computer arrangement. In this lastembodiment, the computer screen can power the ICL electromagneticallywhile the user checks their GPI e-mail.

[0273] Furthermore, diabetics can monitor their disease while playinggolf, and a parent with high blood pressure can have ICLs in their eyesdetecting stroke and heart markers while playing with their children inthe comfort of their homes and without having to spend time, money, andeffort to go to a hospital for testing with drawing of blood as isconventionally done.

[0274] The ICL can besides performing tests in-situ also collect the eyefluid for further analysis as one is working in the office over an eighthour period in a comfortable and undisturbed manner by having the ICL inthe eye lid pocket. In this last exemplary embodiment the user sends theICL to the laboratory for further processing if needed, but stillsampling was done without the user having to go to a doctor, devote timeexclusively for the test, endure pain with a needle stick, endure therisk of infection and the costs associated with the procedure.

[0275] Moreover, the ICL system provides a 24 hour continuoussurveillance system for the presence of, for instance, cancer markersbefore the cancer is clinically identifiable, meaning identified by thedoctor or by symptoms experienced by the patient. The ICL system of thecurrent invention can pump eye fluid and cells into the ICL continuouslyfor many days at a time creating thus a continuous monitoring system andas soon as the marker is identified a signal is transmitted. For exampleif a reaction chamber X in the ICL is coated with electrocatalyticantibodies for a breast cancer marker, then once the marker is presentan electrical signal is created in the chamber X indicating that abreast cancer or prostate cancer for instance was identified.

[0276] Most cancers kill because they are silent and identified onlywhen in advanced stages. Thus the ICL system provides the idealsurveillance system potentially allowing life-expectancy in general toincrease associated with the extra benefit of the obvious decrease inhealth care costs related which occurs when treating complicated andadvanced cancers. In addition, the present invention provides all ofthese life-saving, cost-saving and time-saving features in a painlessmanner without anyone even knowing one is checking for a cancer marker,heart disease marker, infectious agent, blood sugar levels and so forthsince the ICL is conveniently and naturally hidden under the eye lidworking as your Personal invisible Laboratory (PIL).

[0277] It is an object of the present invention to address the aboveneeds in the art and provide the accuracy and precision needed forclinical application by being able to eliminate or substantially reducethe sources of errors, interference, and variability found in the priorart. By greatly reducing or eliminating the interfering constituents andproviding a much higher signal to noise ratio, the present invention canprovide the answers and results needed for accurate and precisemeasurement of chemical components in vivo using optical means such asinfrared spectroscopy. Moreover, the apparatus and methods of thepresent invention by enhancing the signal allows clinical usefulreadings to be obtained with various techniques and using differenttypes of electromagnetic radiation. Besides near-infrared spectroscopy,the present invention provides superior results and higher signal tonoise ratio when using any other form of electromagnetic radiation suchas for example mid-infrared radiation, radio wave impedance,photoacoustic spectroscopy, Raman spectroscopy, visible spectroscopy,ultraviolet spectroscopy, fluorescent spectroscopy, scatteringspectroscopy, and optical rotation of polarized light as well as othertechniques such as fluorescent (including Maillard reaction, lightinduced fluorescence, and induction of glucose fluorescence byultraviolet light), colorimetric, refractive index, light reflection,thermal gradient, Attenuated Total Internal Reflection, molecularimprinting, and the like.

[0278] It is a further object of the present invention to providemethods and apparatus for measuring a substance of interest usingnatural body far-infrared emissions which occur in a thermally stableenvironment such as in the eyelid pocket.

[0279] Still a further object of the invention is to provide anapparatus and method that allows direct application of Beer-Lambert'slaw in-vivo.

[0280] Yet a further object is to provide a method and apparatus forcontinuous measurement of core temperature in a thermally stableenvironment.

[0281] By the present invention, the discovery of plasma present in andon the surface of the conjunctiva can be used for a complete analysis ofblood components. Plasma corresponds to the circulating chemistry of thebody and it is the standard used in laboratories for sample testing.Interstitial fluid for instance is tested in labs only from corpses butnever from a living person.

[0282] Laboratories also do not use whole blood for measuring compoundssuch as for example, glucose. Laboratories separate the plasma and thenmeasure the glucose present in plasma.

[0283] Measurement of glucose in whole blood is subject to many errorsand inaccuracies. For example changes in hematocrit that occurparticularly in women, certain metabolic states, and in many diseasescan have an important effect on the true value of glucose levels.Moreover, the cellular component of blood alters the value of glucoselevels.

[0284] Many of the machines which use whole blood (invasive means usingfinger prick) give a fictitious value which attempts to indicate theplasma value. Measurements in interstitial fluid also give fictitiousvalues which tries to estimate what the plasma values of glucose wouldbe if measured in plasma.

[0285] Measurement of substances in the plasma gives the most accurateand precise identification and concentration of said substances andreflects the true metabolic state of the body. In addition, the opticalproperties of plasma are stable and homogeneous in equivalent samplepopulation.

[0286] Evaluations have been made of the external surfaces and mucosalareas of the human body and only one area has been identified withsuperficial vessels and leakage of plasma. This area with fenestrationsand plasma leakage showed to be suitable for noninvasive measurements.This preferred area is the conjunctival lining of the eye including thetear puncturn lining.

[0287] Another area identified but with leakage of lymphatic fluid is inthe oral mucosa between teeth, but leakage is of only a small amount,not constant, and not coming from superficial vessels with fenestrationsand plasma leakage as it occurs in the conjunctiva.

[0288] The methods and apparatus using superficially flowing plasmaadjacent to the conjunctiva as disclosed in the present inventionprovides an optimal point for diagnostics and a point of maximumdetected value and maximum signal for determination of concentration oridentification of substances independent of the type of electromagneticradiation being directed at or through the substance of interest in thesample.

[0289] These areas in the eye provide plasma already separated from thecellular component of blood with said plasma available superficially onthe surface of the eye and near the surface of the eye. The plasma fillsthe conjunctival interface in areas with blood vessels and without bloodvessels. Plasma flowing through fenestrations rapidly leaks andpermeates the whole conjunctival area, including areas denuded fromblood vessels.

[0290] The plasma can be used for non-invasive or minimally invasiveanalysis, for instance, using chemical, electrochemical, or microfluidicsystems. The conjunctiva and plasma can also be used for evaluation andidentification of substances using electromagnetic means such as withthe optical techniques of the present invention. The measurementprovided by the present invention can determine the concentration of anyconstituent in the eye fluid located adjacent to the conjunctiva. Avariety of optical approaches such as infrared spectroscopy can be usedin the present invention to perform the measurements in the eyeincluding transmission, reflectance, scattering measurement frequencydomain, or for example phase shift of modulated light transmittedthrough the substance of interest, or a combination of these.

[0291] The methods, apparatus, and systems of the present invention canuse spectroscopic analysis of the eye fluid including plasma present on,in, or preferably under the conjunctiva to determine the concentrationof chemical species present in such eye fluid while removing or reducingall actual or potential sources of errors, sources of interference,variability, and artifacts.

[0292] The method and apparatus of the present invention overcomes allof the issues and problems associated with previous techniques anddevices. In accordance with the present invention, plasma containing thesubstance to be measured is already separated and can be used formeasurement including simultaneous and continuous measurement ofmultiple substances present in said plasma or eye fluid. One of theapproaches includes non-invasive and minimally invasive means tooptically measure the substance of interest located in the eye fluidadjacent to the conjunctiva.

[0293] An electromagnetic measurement, such as optical, is based on eyefluid including plasma flowing in a living being on the surface of theeye. The method and apparatus involves directing electromagneticradiation at or through the conjunctiva with said radiation interactingwith the substance of interest and being collected by a detector. Thedata collected is then processed for obtaining a value indicative of theconcentration of the substance of interest.

[0294] It is very important to note that measurements using theelectromagnetic technique as described in the present invention do notrequire any flow of fluid to reach the sensor in order to determine theconcentration of the substance of interest. The system is reagentlessand determination of the concentration of the substance of interest isaccomplished simply by detecting and analyzing radiation that interactswith the substance of interest present adjacent to the conjunctiva

[0295] The method and apparatus of the present invention include forexample glucose measurement in the near infrared wavelength regionbetween 750 and 3000 nm and preferably in the region where the highestabsorption peaks are known to occur, for glucose for example in theregion between 2080 to 2200 nm and for cholesterol centered around 2300nm. The spectral region can also include infrared or visible wavelengthto detect other chemical substances besides glucose or cholesterol.

[0296] The apparatus includes at least one radiation source frominfrared to visible light which interacts with the substance of interestand is collected by a detector. The number and value of theinterrogation wavelengths from the radiation source depends upon thechemical substance being measured and the degree of accuracy required.As the present invention provides reduction or elimination of sources ofinterference and errors, it is possible to reduce the number ofwavelengths without sacrificing accuracy. Previously, the mid-infraredregion has not been considered viable for measurement in humans becauseof the high water absorption that reduces penetration depths to microns.The present invention can use this mid-infrared region since the plasmawith the substance of interest is already separated and located verysuperficially and actually on the surface of the eye which allowssufficient penetration of radiation to measure said substance ofinterest.

[0297] The present invention reduces variability due to tissuestructure, interfering constituents, and noise contribution to thesignal of the substance of interest, ultimately substantially reducingthe number of variables and the complexity of data analysis, either byempirical or physical methods. The empirical methods including PartialLeast squares (PLS), principal component analysis, artificial neuralnetworks, and the like while physical methods include chemometrictechniques, mathematical models, and the like. Furthermore, algorithmswere developed using in-vitro data which does not have extraneous tissueand interfering substances completely accounted for as occurs withmeasurement in deep tissues or with excess background noise such as inthe skin and with blood in vivo. Conversely, standard algorithms forin-vitro testing correlates to the in vivo testing of the presentinvention since the structures of the eye approximates a Lambertiansurface and the conjunctiva is a transparent and homogeneous structurethat can fit with the light-transmission and light-scattering conditioncharacterized by Beer-Lambert's law.

[0298] The enormous amount of interfering constituents, source oferrors, and variables in the sample which are eliminated or reduced withthe present invention include:

[0299] Sample with various layers of tissue

[0300] Sample with scattering tissue

[0301] Sample with random thickness

[0302] Sample with unknown thickness

[0303] Sample with different thickness among different individuals

[0304] Sample that changes in thickness with aging

[0305] Sample that changes in texture with aging

[0306] Sample with keratin

[0307] Sample that changes according to exposure to the environment

[0308] Sample with barriers to penetration of radiation

[0309] Sample that changes according to the local ambient

[0310] Sample with fat

[0311] Sample with cartilage

[0312] Sample with bone

[0313] Sample with muscle

[0314] Sample with high water content

[0315] Sample with walls of vessels

[0316] Sample with non-visible medium that is the source of the signal

[0317] Sample with opaque interface

[0318] Sample interface made out of dead tissue

[0319] Sample with interface that scars

[0320] Sample highly sensitive to pain and touch

[0321] Sample with melanin

[0322] Sample interface with different hue

[0323] Sample with hemoglobin

[0324] Sample medium which is in motion

[0325] Sample medium with cellular components

[0326] Sample with red blood cells

[0327] Sample with uneven distribution of the substance being measured

[0328] Sample with unsteady supply of the substance being measured

[0329] Non-homogeneous sample

[0330] Sample with low concentration of the substance being measured

[0331] Sample surrounded by structures with high-water content

[0332] Sample surrounded by irregular structures

[0333] Sample medium that pulsates

[0334] Sample with various and unknown thickness of vessel walls

[0335] Sample with unstable pressure

[0336] Sample with variable location

[0337] Sample filled with debris

[0338] Sample located deep in the body

[0339] Sample with unstable temperature Sample with thermal gradient

[0340] Sample in no direct contact with thermal energy

[0341] Sample with no active heat transfer

[0342] Sample with heat loss

[0343] Sample influenced by external temperature

[0344] Sample with no-isothermic conditions

[0345] Sample with self-absorption of thermal energy

[0346] An exemplary representation of some of the interferingconstituents present in the sample irradiated that are reduced oreliminated by the present invention.

[0347] a) Radiation directed at a target tissue can be absorbed by thevarious constituents including several layers of the skin, various bloodcellular components, fat, bone, walls of the blood vessel, and the like.This drastically reduces the signal and processing requires subtractingall of those intervening elements. All of the named interferingconstituents in the sample irradiated are eliminated with the presentinvention.

[0348] b) Skin alone as the target tissue creates reduction of signal tonoise because skin by itself is an additional scattering tissue. Thepresent invention eliminates interfering scattering structures in thesample irradiated.

[0349] c) Thickness of the skin (which includes the surface of thetongue) is random within the same individual even in an extremely smallarea with changes in thickness depending on location. It is verydifficult to know the exact thickness of the skin from point to pointwithout histologic (tissue removal) studies. There is great variabilityin signal due to skin thickness. All of those sources of errors andvariability such as random thickness and unknown thickness of thestructure in the sample irradiated are eliminated.

[0350] d) Thickness of the skin also varies from individual toindividual at the exact same location in the skin and thus the signalhas to be individually considered for each living being. Individualvariation in thickness of the structure in the sample irradiated is alsoeliminated.

[0351] e) Changes in texture and thickness in the skin that occurs withaging have a dramatic effect in acquiring accurate measurements. Changesin texture and thickness due to aging of the structure in the sampleirradiated are also eliminated.

[0352] f) Changes in the amount of keratin in the skin and tongue liningwhich occurs in different metabolic and environmental conditions alsoprevent accurate signal acquisition. Keratin and variability in thesample irradiated are both also eliminated.

[0353] g) Skin structure such as amount of elastin also varies greatlyfrom person to person, according to the amount of sun exposure,pollution, changes in the ozone layer, and other environmental factorswhich lead to great variability in signal acquisition. There iselimination of the sample irradiated being susceptible to most of theenvironmental factors by being naturally shielded from saidenvironmental factors.

[0354] h) Due to the structure and thickness of the skin the radiationcan fail to penetrate and reach the location in which the substance ofinterest is present. There is elimination of a structure in the sampleirradiated that can work as a barrier to radiation.

[0355] i) Measurements are also affected by the day-to-day variations inskin surface temperature and hydration in the same individual accordingto ambient conditions and metabolic status of said individual. There iselimination of structures in the sample irradiated that is susceptibleto changes in temperature and hydration according to ambient conditions.

[0356] j) The intensity of the reflected or transmitted signal can varydrastically from patient to patient depending on the individual physicalcharacteristics such as the amount of fat. A thin and obese person willvary greatly in the amount of fat and thus will vary greatly in theradiation signal for the same concentration of the substance ofinterest. There is elimination of fat in the sample area beingirradiated.

[0357] k) The amount of protein such as muscle mass also varies greatlyfrom person to person. There is elimination of muscle mass variabilityin the sample area being irradiated.

[0358] l) The level of water content and hydration of skin andsurrounding structures varies, from individual to individual and in thesame individual over time with evaporation. There is elimination ofvariability from person to person and over time due to changes in waterevaporation in the sample area being irradiated.

[0359] m) Thickness and texture of walls of blood vessels also changesubstantially with aging and greatly vary from location to location.There is elimination in the sample being irradiated of signalvariability due to presence of walls which change substantially withaging and location.

[0360] n) The deep blood vessels location and structure within the sameage group still varies greatly from person to person and anatomicvariation is fairly constant with different depth and location of bloodvessel in each individual. Since those blood vessels are located deepand covered by an opaque structure like the skin it is impossible toprecisely determine the position of said blood vessels. There iselimination of source medium for the signal which is not visible duringirradiation of the sample.

[0361] The use of conjunctiva and plasma present adjacent to saidconjunctiva and the eyelid pocket provides an optimum location formeasurement by electromagnetic means in a stable environment which isundisturbed by internal or external conditions.

[0362] Signal to noise is greatly improved since the thin transparentconjunctiva is the only intervening tissue in the optical path to betraversed from source to detector.

[0363] The conjunctiva does not age like the skin or blood vessels. Boththe thickness and texture of the conjunctiva remain without majorchanges throughout the lifespan of a person. That can be easily noted bylooking at the conjunctiva of a normal person but with different ages,such as a 25 year old and a 65 year old person.

[0364] The conjunctiva is a well vascularized tissue, but still leavesmost of its area free from blood vessels which allows measurement ofplasma to be performed without interference by blood components. Thoseareas free of vessels are easily identified and the eyeball of a normalperson is white with few blood vessels. Furthermore, the conjunctiva inthe cul-de-sac rim is free of blood vessels and plasma is collectedthere due to gravity, and measurement of substance of interest in thecul-de-sac is one of the preferred embodiments of the present invention.

[0365] Moreover, the conjunctiva is capable of complete regenerationwithout scarring. Furthermore, the conjunctiva can provide easy couplingwith the surface of the sensing means since the conjunctiva surface is aliving tissue contrary to the skin surface and tongue lining which ismade out of dead tissue (keratin). In addition, the conjunctiva iseasily accessible manually or surgically. Besides, the conjunctiva hasonly a few pain fibers and no tactile fibers creating minimal sensationto touch and to any hardware in contact with the conjunctival tissue.

[0366] Skin has various layers with random and inconstant thickness. Theskin has several layers including: the epidermis which varies inthickness depending on the location from approximately 80 to 250μ, thedermis with thickness between approximately 1 to 2 mm, and thesubcutaneous tissue which varies substantially in thickness according toarea and physical constitution of the subject and which falls in thecentimeter range reaching various centimeters in an obese person. Theconjunctiva is a few micrometers thick mono-layer structure withconstant thickness along its entire structure. The thickness of theconjunctiva remains the same regardless of the amount of body fat.Normal conjunctiva does not have fat tissue.

[0367] In the present invention the superficial and the only interfaceradiated, involves the conjunctiva, a very thin layer of transparenthomogenous epithelial tissue. Wavelengths of less than 2000 nm do notpenetrate well through skin. Contrary to that, due to the structure andthickness of the conjunctiva, a broad range of wavelengths can be usedand will penetrate said conjunctiva.

[0368] Melanin is a cromophore and there is some amount of melanin inthe skin of all normal individuals, with the exception of pathologicstatus as in complete albinos. The skin with melanin absorbsnear-infrared light which is the spectral region of interest innear-infrared spectroscopy and the region, for example, where glucoseabsorbs light. The present invention eliminates surface barriers andsources of error and variability such as melanin present in the skin andwhich varies from site to site and from individual to individual. Normalconjunctiva does not have melanin.

[0369] There are variations from person to person in thickness and colorof skin and texture of skin. Normal conjunctiva is transparent in allnormal individuals and has the equivalent thickness and texture.

[0370] The present invention eliminates enormous sample variability dueto location as occur in the skin with different thickness and structureaccording to the area measured in said skin. The conjunctiva is a thinand homogeneous tissue across its entire surface area.

[0371] There is elimination of variability due to changes in texture andstructure as occur in the skin due to aging. The conjunctiva ishomogeneous and does not age like the skin. There is also elimination ofvariability found in the skin surface due to the random presence ofvarious glands such as sweat glands, hair follicles, and the like.

[0372] There is elimination of an optically-opaque structure like theskin. It is very difficult to apply Beer-Lambert's law when using theskin. The law describes the relationship between light absorption andconcentration and according to Beer-Lambert's law the absorbance of aconstituent is proportional to its concentration in solution. Theconjunctiva is a transparent and homogeneous structure which can fitwith the light-transmission and light-scattering phenomena characterizedby Beer-Lambert's law.

[0373] There is elimination of interfering constitutes and lightscattering elements such as fat, bone, cartilage and the like. Theconjunctiva does not have a fat layer and radiation does not have to gothrough cartilage or bone to reach the substance of interest.

[0374] In the present invention the conjunctiva, which is a thinmono-layer transparent homogeneous structure, is the only interferingtissue before radiation reaches the substance of interest alreadyseparated and collected in the plasma adjacent to said conjunctiva.Since the conjunctiva does not absorb the near-infrared light there isno surface barrier as an interfering constituent and since theconjunctiva is very thin and homogeneous there is minimal scatteringafter penetration.

[0375] In addition, the temperature in the eye is fairly constant andthe pocket in the eyelid offers a natural and thermally sealed pocketfor placement of sensing means.

[0376] Presence of whole blood and other tissues such as skin scatterslight and further reduces the signal. The present invention eliminatesabsorption interference by cromophores such as hemoglobin such aspresent in whole blood. Radiation can be directed at the conjunctivalarea free of blood and hemoglobin, but with plasma collected underneath.Thus another source of error is eliminated as caused by confusion ofhemoglobin spectra with glucose spectra.

[0377] The reflective or transmissive measurements of the presentinvention involve eye fluid and plasma adjacent to the conjunctiva whichcreates the most homogeneous medium and provides signal to noise usefulfor clinical applications. The present invention provides plasma whichis the most accurate and precise medium for measuring and identifyingsubstances. The present invention provides said plasma covered only bythe conjunctiva which is a structure which does not absorb near-infraredlight.

[0378] The plasma is virtually static or in very slow motion as underthe conjunctiva which creates a stable environment for measurement.

[0379] The plasma present in the eye provides a sample free of bloodconstituents which are source of errors and scattering. The plasma beingirradiated is free of major cellular components and it is homogeneouswith minimal scattering.

[0380] The background where the plasma is collected includes the sclerawhich is a homogeneous and white reflective structure with virtually nowater contained in its layers. Thus, there is also elimination ofsurrounding tissue composed by large amounts of water.

[0381] The present invention eliminates light being radiated through atissue with varying amounts of glucose depending on the location such asthe skin with the epidermis, dermis and subcutaneous having differentconcentrations of glucose. In the present invention glucose is evenlydistributed in the plasma adjacent to the conjunctiva.

[0382] The plasma present in the eye is a great source of undisturbedand stable signal for glucose as the eye requires a stable supply ofglucose since glucose is the only source of energy that can be used bythe retina. The retina requires a steady supply of glucose for properfunctioning and to process visual information. The eye has a stablesupply of glucose and a relative increase in the amount of the substanceof interest such as for example glucose which increases the signal tonoise ratio and allows fewer wavelengths to be used in order to obtainmeasurements.

[0383] The eye also has the highest amount of blood per gram of tissuein the whole body and thus provide a continuous supply of blood at highrate which is delivered as plasma through the conjunctival vessels.

[0384] The concentration of chemical substances in the plasma are highin relation to the whole sample allowing a high signal to noise ratio tobe acquired. Glucose is found in very dilute quantities in whole bloodand interstitial fluid but it is relatively concentrated in the plasmaproviding a higher signal as found in the surface of the eye. In complexmedia such as the blood where there is a great number of overlappingsubstances, the number of required wavelengths increases substantially.In a homogenous sample such as the plasma adjacent to the conjunctiva,the reduction in the number of wavelengths does not affect accuracy. Inaddition, it is difficult for a detector to identify the glucoseabsorption peak due to the variability in scatter as occurs with blood.The present invention can rely on more cost-effective detectors as theabsorption peak in the plasma sample can be more easily identified.

[0385] Due to the presence of minimal interfering components and highsignal to noise ratio, the present invention can detect lower glucoselevels (hypoglycemia). The strength of signal for the substance ofinterest is a function of the concentration and the homogeneity of thesample. Blood and other tissues are highly non-homogeneous. Contrary tothat the plasma is highly homogeneous and with higher concentration ofthe substance of interest in relation to the total sample.

[0386] There is elimination of a very low signal source with greatbackground noise as it occurs in the aqueous humor of the eye. Plasmagenerates a high signal due to the relative high concentration of thesubstance of interest already naturally separated from cellularcomponents and with minimal background noise.

[0387] There is reduction in the amount of interfering elements such aswater. The present invention includes water displacement both passivelyand actively. Passive displacement is observed when the concentration ofthe substance of interest increases as found in the plasma adjacent tothe conjunctiva which decreases water interference and the sample issurrounded by the sclera which is a structure which does not containwater. Active displacement is observed when artificially using ahydrophobic surface for the contact device which displaces water fromthe surface of the tissue creating a dry interface.

[0388] There is elimination of structural and absorption backgroundirregularities as occur in the skin, inside of the eye, blood vessels,and the like. The conjunctiva is positioned against a smooth whitehomogeneous water-free surface, the sclera.

[0389] There is elimination of variability due to the direct pulsationof the wall of blood vessel. Blood by nature is constantly in rapidmotion and such rapid motion can create significant variability in themeasurements. The present invention eliminates error and variability duerapid motion of the sample as occurs in blood vessels. Plasma flowscontinuously through fenestrations but not in a pulsatile manner. Theplasma collected adjacent to the conjunctiva has insignificant pulsatingcontent.

[0390] There is elimination of an important source of variability asoccur in moving blood with cellular components in a blood vessel whichis not homogeneous and creates further scattering. Plasma flowscontinuously through fenestrations but without cellular components.

[0391] Many and rapid changes occur in flowing blood inside a bloodvessel. Due to this phenomena the resulting spectra has to be acquiredin an extremely short period of time which is done in an attempt todecrease the number of artifacts and source of errors. Due to the poorsignal created by the various and rapid changes in flow, measurementshave to be repeated several times within a very short period of time andthe total averaged. This leads to complicated construction of devicesand controlling systems, but still only delivering a poor signal tonoise. The present invention allows the spectra to be acquired overlonger periods of time and without the need for such repeat measurementssince there is minimal background noise and interfering constituents.This, therefore, allows lower cost and more efficient systems to be madeand used.

[0392] There are variations from person to person in thickness andtexture of blood vessel walls. There is also variability due to changesin texture and structure that occur in the vessel wall due to aging. Theapparatus and methods of the present invention include directingradiation that does not need to penetrate through the wall of bloodvessels to acquire the signal for the substance of interest. Therefore,the above source of errors and variability are eliminated.

[0393] There is reduction or elimination of variability and error due tochanges in pressure between the sensor interface and the tissue. Manyerrors occur when techniques require placement of a body part againstthe sensor in which the subject or the operator is artificially applyingthe pressure. An example is when a subject applies his/her skin againstthe sensor or an operator grasps the tongue or finger of a subject. Thepressure applied by either the subject or the operator variessubstantially over time and from measurement to measurement and fromsubject to subject and from operator to operator. The interface betweenthe tissue and sensor changes continuously with contact pressure andmanipulation by the subject or operator since those structures such asskin and tongue have several layers that change and yield in reaction toapplied pressure. Even if pressure controlled systems are used, there issignificant variation because of the different texture and thicknessfrom individual to individual, from location to location, and in thesame individual over time which prevents precise measurements from beingacquired.

[0394] One of the preferred embodiments of the present invention whichuses a contact device in the eyelid pocket eliminates this variation inpressure. The pressure applied by the eyelid in the resting state isfairly constant and equal in normal subjects with a horizontal force of25,000 dynes and a tangential force of 50 dynes. Furthermore, the otherembodiments which do not use a contact device in the eyelid pocket, canuse a probe resting on the surface of the tissue and also obtainaccurate measurements. Examples of those devices are slit-lamps whichcan be used for precise application of pressure against the surface ofthe eye and since the thickness and texture of the conjunctiva ishomogeneous, accurate and precise measurement can be obtained.

[0395] Depending on the amount and time of exposure, infrared radiationdirected at the tissue such as skin may prove uncomfortable and promoteunwanted heating and or damage to the surface irradiated. In the presentinvention the substance of interest is separated from most of thebackground noise and is located superficially and thus less radiationcan be used without affecting accuracy. The present invention enhancessignal to noise ratio without increasing the amount of radiation emittedand the increased risk of burning the surface being radiated.

[0396] Inconsistency in the location of the source and detector can bean important source of error and variability. The eyelid pocket providesa confined environment of fixed dimensions that provides a natural meansfor providing the consistency needed for accurate measurements. Inaddition, the measurements are much less sensitive to sensor locationsince the structure of the conjunctiva is homogeneous and the sensorsurface can rest and adhere to the conjunctival surface. The use of ahydrophobic surface in the contact device encasing the radiation sourceand detector means promotes adherence to the conjunctival surfacefurther allowing precise positioning.

[0397] The present invention also discloses minimally invasivetechniques for placement of systems under the conjunctiva that uses onlyone drop of anesthetic for the procedure. The conjunctiva is the onlysuperficial place in the body that allows painless surgical implantationof hardware to be done using simply one drop of anesthetic. Thus, thepresent invention eliminates the need for high-risk surgical proceduresand internal infection. In the minimally invasive embodiment, the deviceimplanted is located and implanted superficially and can be easilyremoved using just one drop of anesthetic.

[0398] Conjunctiva is transparent and thus the implant procedure can bedone under direct view. The bulbar conjunctiva is not adherent tounderlying tissues and there is a natural space underneath saidconjunctiva allowing easy view for placement and removal of an implantedsource/detector pair. Thus, there is elimination of the need tosurgically implant devices deep in the body such as around blood vesselsand inside the abdomen. There is elimination of implanting devicesblindly since the skin is not transparent. There is elimination of amajor surgical procedure in case of removal from inside the vessels,around the vessels, or inside the body.

[0399] In relation to the minimally invasive embodiment in which theoptical sensor system is placed under the conjunctiva, the presentinvention provides a sample, such as plasma, which is free from debris.In the minimally invasive embodiment of the present invention, thesystem is measuring glucose already separated and present in the plasmacollected adjacent to the sensor.

[0400] Body temperature such as is found in the surface of the skin isvariable according to the environment and shift of spectra can occurwith changes in temperature. The eyelid pocket provides an optimumlocation for temperature measurement which has a stable temperature andwhich is undisturbed by the ambient conditions. The conjunctival arearadiated has a stable temperature derived from the carotid artery.Moreover, when the embodiment uses a contact device which is located inthe eyelid pocket, there is a natural, complete thermal seal and stablecore temperature. Good control of the temperature also providesincreased accuracy and if desired, reduction of the number ofwavelengths. Besides, the stable temperature environment allows use ofthe natural body infrared radiation emission as means to identify andmeasure the substance of interest.

[0401] Far-infrared radiation spectroscopy measures natural thermalemissions after said emissions interact and are absorbed by thesubstance of interest at the conjunctival surface. The present inventionprovides a thermally stable medium, insignificant number of interferingconstituents, and the thin conjunctival lining is the only structure tobe traversed by the thermal emissions from the eye before reaching thedetector. Thus there is higher accuracy and precision when convertingthe thermal energy emitted as heat by the eye into concentration of thesubstance of interest.

[0402] The ideal thermal environment provided by the conjunctiva in theeyelid pocket can be used for non-invasive evaluation of bloodcomponents besides the measurement of temperature. Far-infraredspectroscopy can measure absorption of far-infrared radiation containedin the natural thermal emissions present in the eyelid pocket. Naturalspectral emissions of infrared radiation by the conjunctiva and vesselsinclude spectral information of blood components. The long wavelengthemitted by the surface of the eye as heat can be used as the source ofinfrared energy that can be correlated with the identification andmeasurement of the concentration of the substance of interest. Infraredemission traverses only an extremely small distance from the eye surfaceto the sensor which means no attenuation by interfering constituents.

[0403] Spectral radiation of infrared energy from the surface of the eyecan correspond to spectral information of the substance of interest.These thermal emissions irradiated as heat at 38 degrees Celsius caninclude the 4,000 to 14,000 nm wavelength range. For example, glucosestrongly absorbs light around the 9,400 nm band. When far-infrared heatradiation is emitted by the eye, glucose will absorb part of theradiation corresponding to its band of absorption. Absorption of thethermal energy by glucose bands is related in a linear fashion to bloodglucose concentration in the thermally sealed and thermally stableenvironment present in the eyelid pocket.

[0404] The natural spectral emission by the eye changes according to thepresence and concentration of a substance of interest. The far-infraredthermal radiation emitted follow Planck's Law and the predicted amountof thermal radiation can be calculated. Reference intensity iscalculated by measuring thermal energy absorption outside the substanceof interest band. The thermal energy absorption in the band of substanceof interest can be determined via spectroscopic means by comparing themeasured and predicted values at the conjunctiva/plasma interface. Thesignal is then converted to concentration of the substance of interestaccording to the amount of thermal energy absorbed.

[0405] The Intelligent Contact Lens in the eyelid pocket providesoptimal means for non-invasive measurement of the substance of interestusing natural heat emission by the eye. Below is an exemplaryrepresentation of various unique advantages and features provided by thepresent invention.

[0406] higher signal as found in the plasma/conjunctiva interface due toless background interference

[0407] undisturbed signal since the heat source is in direct appositionto the sensing means

[0408] stable temperature since the eyelid pocket is thermally sealed

[0409] the eyelid pocket functions as a cavity since the eyelid edge istightly opposed to the surface of the eyeball easily observed in theeye. To see the inside of the eyelid pocket it is necessary to activelypull the eyelid.

[0410] there is no heat loss inside the cavity

[0411] there is active heat transfer from the vessels caused by localblood flow in direct contact with the sensor

[0412] the temperature of the eye, by being supplied directly from thecentral nervous system circulation, is in direct equilibrium with coretemperature.

[0413] Temperature is proportional to blood perfusion. The conjunctivais extremely vascularized and the eye is the organ in the whole bodywith the highest amount of blood per gram of tissue. The conjunctiva isa thin homogeneous layer of equal composition and the eyelid pocket is asealed thermal environment without cooling of surface layers. The bloodvessels in the conjunctiva are branches of the carotid artery comingdirectly from the central nervous system which allows measuring theprecise core temperature of the body.

[0414] The eyelid pocket provides a sealed and homogeneous thermalenvironment. When the eyelids are closed (during blinking or with eyesclosed) or at any time inside the eyelid pockets, the thermalenvironment of the eye exclusively corresponds to the core temperatureof the body. In the eyelid pocket there is prevention of passive heatloss in addition to associated active heat transfer since theconjunctiva is a thin lining of tissue free of keratin and withcapillary level on the surface.

[0415] Skin present throughout the body, including the tongue, iscovered with keratin, a dead layer of thick tissue that alterstransmission of infrared energy emitted as heat. The conjunctiva doesnot have a keratin layer and the sensor can be placed in intimatethermal contact with the blood vessels.

[0416] Skin with its various layers and other constituents selectivelyabsorb infrared energy emitted by deeper layers before said energyreaches the surface of said skin. Contrary to that, the conjunctiva ishomogeneous with no absorption of infrared energy and the blood vesselsare located on the surface. This allows undisturbed delivery of infraredenergy to the surface of the conjunctiva and to a temperature detectorsuch as an infrared detector placed in apposition to said surface of theconjunctiva.

[0417] In the skin and other superficial parts of the body there is athermal gradient with the deeper layers being warmer than thesuperficial layers. In the conjunctiva there is no thermal gradientsince there is only a mono-layer of tissue with vessels directlyunderneath. The thermal energy generated by the conjunctival bloodvessels exiting to the surface corresponds to the undisturbed coretemperature of the body.

[0418] The surface temperature of the skin and other body parts does notcorrespond to the blood temperature. The surface temperature in the eyecorresponds to the core temperature of the body.

[0419] Thus, skin is not suitable for creating a thermally sealed andstable environment for measuring temperature and the concentration ofthe substance of interest. Most important, no other part of the body,but the eye provides a natural pocket structure for direct apposition ofthe temperature sensor in direct contact with the surface of the bloodvessel. The conjunctiva and eyelid pocket provides a thermally sealedenvironment in which the temperature sensor is in direct apposition tothe heat source. Moreover, in the eyelid pocket thermal equilibrium isachieved immediately as soon as the sensor is placed in said eyelidpocket and in contact with the tissue surface.

[0420] The method and apparatus of the present invention providesoptimal means for measurement of the concentration of the substance ofinterest from the infrared energy emissions by the conjunctival surfaceas well as evaluation of temperature with measurement of coretemperature.

[0421] The temperature sensor, preferably a contact thermosensor, ispositioned in the sealed environment provided by the eyelid pocket,which eliminates spurious readings which can occur by accidental readingof ambient temperature.

[0422] The apparatus uses the steps of sensing the level of temperature,producing output electrical signals representative of the intensity ofthe radiation, converting the resulting input, and sending the convertedinput to a processor. The processor is adapted to provide the necessaryanalysis of the signal to determine the temperature and concentration ofthe substance of interest and displaying the temperature level and theconcentration of the substance of interest.

[0423] The apparatus can provide core temperature, undisturbed by theenvironment, and continues measurement in addition to far-infraredspectroscopy analysis for determining the concentration of the substanceof interest with both single or continuous measurement.

[0424] The present invention includes means for directing preferablynear-infrared energy into the surface of the conjunctiva, means foranalyzing and converting the reflectance or back scattered spectrum intothe concentration of the substance of interest and means for positioningthe light source and detector means adjacent to the surface of the eye.The present invention also provides methods for determining theconcentration of a substance of interest with said methods including thesteps of using eye fluid including plasma present on, in, or below theconjunctiva, directing electromagnetic radiation such as near-infraredat the plasma interface, detecting the near-infrared energy radiatedfrom said plasma interface, taking the resulting spectra and providingan electrical signal upon detection, processing the signal and reportingconcentration of the substance of interest according to said signal. Theinvention also includes means and methods for positioning the lightsources and detectors in stable position and with stable pressure andtemperature in relation to the surface to which radiation is directed toand received from. The plasma collected underneath the conjunctiva ispreferably used as the source medium for determination of theconcentration of the substance of interest.

[0425] The present invention further includes means for directingnear-infrared energy through the conjunctiva/plasma interface, means forpositioning radiation source and detector diametrically opposed to eachother, and means for analyzing and converting the transmitted resultingspectrum into the concentration of the substance of interest. Thepresent invention also provides methods for determining theconcentration of a substance of interest with said methods including thesteps of using eye fluid including plasma adjacent to the conjunctiva asthe source medium for measuring the substance of interest, directingelectromagnetic radiation such as near-infrared through theconjunctiva/plasma interface, collecting the near-infrared energyradiated from said conjunctiva/plasma interface, taking the resultingspectra and providing an electrical signal upon detection, processingthe signal and reporting concentration of the substance of interestaccording to said signal. The invention also includes means and methodsfor positioning the radiation sources and detectors in a stable positionand with stable pressure and temperature in relation to the surface towhich radiation is directed through.

[0426] The present invention yet includes means for collecting naturalfar-infrared radiation emitted as heat from the eye, means forpositioning a radiation collector to receive said radiation, and meansfor converting the collected radiation from the eye into theconcentration of the substance of interest. The present invention alsoprovides methods for determining the concentration of the substance ofinterest with said methods including the steps of using the naturalfar-infrared emission from the eye as the resulting radiation formeasuring the substance of interest, collecting the resulting radiationspectra in a thermally stable environment, providing an electricalsignal upon detection, processing the signal and reporting theconcentration of the substance of interest according to said signal. Athermally stable environment includes open eye or closed eye. Thethermal emission collection means are in contact with the conjunctiva inthe eyelid pocket with eyes open or closed.

[0427] With closed eye, the collection means can also be in contact withthe cornea. With closed eyes the cornea is in equilibrium with theaqueous humor inside the eye with transudation of fluid to the surfaceof the cornea. The cornea during closed eyes or blinking is in thermalequilibrium with core body temperature. When the eyes are closed theequilibrium created allows the evaluation of substances of interestusing a contact lens with optical or electrochemical sensors placed onthe surface of the cornea. The invention also includes means and methodsfor positioning the thermal emission collection means in a stableposition and with stable pressure and with eyes open or closed.

[0428] The present invention further includes measuring the coretemperature of the body, both single and continuous measurements. Thepresent invention includes means for collecting thermal radiation fromthe eye, means for positioning temperature sensitive devices to receivethermal radiation from the eye in a thermally stable environment, andmeans for converting said thermal radiation into the core temperature ofthe body. The present invention also provides methods for determiningcore temperature of the body with said methods including the steps ofusing thermal emissions from the eye in a thermally stable environment,collecting the thermal emission by the eye, providing an electricalsignal upon detection, processing the signal and reporting thetemperature level. The invention also includes means and methods forproper positioning of the temperature sensor in a stable position andwith stable pressure as achieved in the eyelid pocket. The invention yetincludes means to monitor a bodily function and dispense medications oractivate devices according to the signal acquired. The invention furtherincludes apparatus and methods for treating vascular abnormalities andcancer. The invention further includes means to dispense medications.

[0429] Substances of interest can include any substance present adjacentto the conjunctiva or surface of the eye which is capable of beinganalyzed by electromagnetic means. For example but not by way oflimitation such substances can include any substance present in plasmasuch as molecular, chemical or cellular, and for example exogenouschemicals such as drugs and alcohol as well as endogenous chemicals suchas glucose, oxygen, bicarbonate, cardiac markers, cancer markers,hormones, glutamate, urea, fatty acids, cholesterol, triglycerides,proteins, creatinine, aminoacids and the like and cellular constituentssuch as cancer cells, and the like. Values such as pH can also becalculated as pH can be related to light absorption using reflectancespectroscopy.

[0430] Substances of interest can also include hemoglobin, cytochromes,cellular elements and metabolic changes corresponding to lightinteraction with said substances of interest when directingelectromagnetic radiation at said substances of interest. All of thoseconstituents and values can be optimally detected in the conjunctiva orsurface of the eye using electromagnetic means and in accordance withtheir optical, physical, and chemical characteristics.

[0431] For the purpose of the description herein, the sclera isconsidered as one structure. It is understood however, that the sclerahas several layers and surrounding structures including the episcleraand Tenon's capsule.

[0432] For the purpose of the description herein, light and radiationare used interchangeably and refers to a form of energy contained withinthe electromagnetic spectrum.

[0433] The eye fluid, conjunctival area, methods and apparatus asdisclosed by the present invention provides ideal means and sources ofsignals for measurement of any substance of interest allowing optimaland maximum signals to be obtained. The present invention allowsanalytical calibration since the structure and physiology of theconjunctiva is stable and the amount of plasma collected adjacent to theconjunctiva is also stable. This type of analytical calibration can beuniversal which avoids clinical calibration that requires blood samplingindividually as a reference.

[0434] The foregoing and other objects, features, aspects and advantagesof the present invention will become more apparent from the followingdetailed description of the present invention when taken in conjunctionwith the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0435]FIG. 1 is a schematic block diagram illustrating a system formeasuring intraocular pressure in accordance with a preferred embodimentof the present invention.

[0436] FIGS. 2A-2D schematically illustrate a preferred embodiment of acontact device according the present invention.

[0437]FIG. 3 schematically illustrates a view seen by a patient whenutilizing the system illustrated in FIG. 1.

[0438]FIGS. 4 and 5 schematically depict multi-filter optical elementsin accordance with a preferred embodiment of the present invention.

[0439] FIGS. 5A-5F illustrate a preferred embodiment of an applicatorfor gently applying the contact device to the cornea in accordance withthe present invention.

[0440]FIG. 6 illustrates an exemplary circuit for carrying out severalaspects of the embodiment illustrated in FIG. 1.

[0441]FIGS. 7A and 7B are block diagrams illustrating an arrangementcapable compensating for deviations in corneal thickness according tothe present invention.

[0442]FIGS. 8A and 8B schematically illustrate a contact deviceutilizing barcode technology in accordance with a preferred embodimentof the present invention.

[0443]FIGS. 9A and 9B schematically illustrate a contact deviceutilizing color detection technology in accordance with a preferredembodiment of the present invention.

[0444]FIG. 10 illustrates an alternative contact device in accordancewith yet another preferred embodiment of the present invention.

[0445]FIGS. 11A and 11B schematically illustrate an indentation distancedetection arrangement in accordance with a preferred embodiment of thepresent invention.

[0446]FIG. 12 is a cross-sectional view of an alternative contact devicein accordance with another preferred embodiment of the presentinvention.

[0447] FIGS. 13A-15 are cross-sectional views of alternative contactdevices in accordance with other embodiments of the present invention.

[0448]FIG. 16 schematically illustrates an alternative embodiment of thesystem for measuring intraocular pressure by applanation, according tothe present invention.

[0449]FIG. 16A is a graph depicting force (F) as a function of thedistance (x) separating a movable central piece from the pole of amagnetic actuation apparatus in accordance with the present invention.

[0450]FIG. 17 schematically illustrates an alternative optical alignmentsystem in accordance with the present invention.

[0451]FIGS. 18 and 19 schematically illustrate arrangements for guidingthe patient during alignment of his/her eye in the apparatus of thepresent invention.

[0452]FIGS. 20A and 20B schematically illustrate an alternativeembodiment for measuring intraocular pressure by indentation.

[0453]FIGS. 21 and 22 schematically illustrate embodiments of thepresent invention which facilitate placement of the contact device onthe sclera of the eye.

[0454]FIG. 23 is a plan view of an alternative contact device which maybe used to measure episcleral venous pressure in accordance with thepresent invention.

[0455]FIG. 24 is a cross-sectional view of the alternative contactdevice which may be used to measure episcleral venous pressure inaccordance with the present invention.

[0456]FIG. 25 schematically illustrates an alternative embodiment of thepresent invention, which includes a contact device with a pressuretransducer mounted therein.

[0457]FIG. 25A is a cross-sectional view of the alternative embodimentillustrated in FIG. 25.

[0458]FIG. 26 is a cross-sectional view illustrating the pressuretransducer of FIG. 25.

[0459]FIG. 27 schematically illustrates the alternative embodiment ofFIG. 25 when located in a patient's eye.

[0460]FIG. 28 illustrates an alternative embodiment wherein two pressuretransducers are utilized.

[0461]FIG. 29 illustrates an alternative embodiment utilizing acentrally disposed pressure transducer.

[0462]FIG. 30 illustrates a preferred mounting of the alternativeembodiment to eye glass frames.

[0463]FIG. 31 is a block diagram of a preferred circuit defined by thealternative embodiment illustrated in FIG. 25.

[0464]FIG. 32 is a schematic representation of a contact device situatedon the cornea of an eye with lateral extensions of the contact deviceextending into the sclera sack below the upper and lower eye lids andillustrating schematically the reception of a signal transmitted from atransmitter to a receiver and the processes performed on the transmittedsignal.

[0465]FIG. 33A is an enlarged view of the contact device shown in FIG.32 with further enlarged portions of the contact device encircled inFIG. 33A being shown in further detail in FIGS. 33B and 33C.

[0466]FIG. 34 is a schematic block diagram of a system of obtainingsample signal measurements and transmitting and interpreting the resultsof the sample signals.

[0467]FIGS. 35A and 35C schematically represent the actuation of thecontact device of the present invention by the opening and closing ofthe eye lids. FIG. 35B is an enlarged detail view of an area encircledin FIG. 35A.

[0468]FIGS. 36A through 36J schematically illustrate various shapes of acontact device incorporating the principles of the present invention.

[0469]FIGS. 37A and 37B schematically illustrate interpretation ofsignals generated from the contact device of the present invention andthe analysis of the signals to provide different test measurements andtransmission of this data to remote locations, such as an intensive careunit setting.

[0470]FIG. 38A schematically illustrates a contact device of the presentinvention with FIG. 38B being a sectional view taken along the sectionline shown in FIG. 38A.

[0471]FIG. 39A illustrates the continuous flow of fluid in the eye. FIG.39B schematically illustrates an alternative embodiment of the contactdevice of the present invention used under the eyelid to produce signalsbased upon flow of tear fluid through the eye and transmit the signalsby a wire connected to an external device.

[0472]FIG. 40A schematically illustrates an alternative embodiment ofthe present invention, used under the eye lid to produce signalsindicative of sensed glucose levels which are radio transmitted to aremote station followed by communication through a publically availablenetwork.

[0473]FIG. 40B schematically illustrates an alternative embodiment ofthe glucose sensor to be used under the eyelid with signals transmittedthrough wires.

[0474]FIG. 41 illustrates an oversized contact device including aplurality of sensors.

[0475]FIG. 42A illustrates open eye lids positioned over a contactdevice including a somnolence awareness device, whereas FIG. 42Billustrates the closing of the eyelids and the production of a signalexternally transmitted to an alarm device.

[0476]FIG. 43 is a detailed view of a portion of an eyeball including aheat stimulation transmission device.

[0477]FIG. 44 is a front view of a heat stimulation transmission devicemounted on a contact device and activated by a remote hardware device.

[0478]FIG. 45 illustrates a band heat stimulation transmission devicefor external use or surgical implantation in any part of the body.

[0479]FIG. 46 illustrates a surgically implantable heat stimulationtransmission device for implantation in the eye between eye muscles.

[0480]FIG. 47 illustrates a heat stimulation device for surgicalimplantation in any part of the body.

[0481]FIG. 48 schematically illustrates the surgical implantation of anoverheating transmission device adjacent to a brain tumor.

[0482]FIG. 49 illustrates the surgical implantation of an overheatingtransmission device adjacent to a kidney tumor.

[0483]FIG. 50 illustrates an overheating transmission device and itsvarious components.

[0484]FIG. 51 illustrates the surgical implantation of an overheatingtransmission devices adjacent to an intraocular tumor.

[0485]FIG. 52 schematically illustrates the surgical implantation of anoverheating transmission device adjacent to a lung tumor.

[0486]FIG. 53 schematically illustrates the positioning of anoverheating transmission device adjacent to a breast tumor.

[0487]FIG. 54A is a side sectional view and FIG. 54B is a front view ofa contact device used to detect chemical compounds in the aqueous humorlocated on the eye, with FIG. 54C being a side view thereof.

[0488]FIG. 55A schematically illustrates a microphone or motion sensormounted on a contact device sensor positioned over the eye for detectionof heart pulsations or sound and transmission of a signal representativeof heart pulsations or sound to a remote alarm device with FIG. 55Bbeing an enlarged view of the alarm device encircled in FIG. 55A.

[0489]FIG. 56 illustrates a contact device with an ultrasonic dipolarsensor, power source and transmitter with the sensor located on theblood vessels of the eye.

[0490]FIG. 57 schematically illustrates the location of a contact devicewith a sensor placed near an extraocular muscle.

[0491]FIG. 58A is a side sectional view illustrating a contact devicehaving a light source for illumination of the back of the eye.

[0492]FIG. 58B illustrates schematically the transmission of light froma light source for reflection off a blood vessel at the cup of the opticnerve and for receipt of the reflected light by a multioptical filtersystem separated from the reflecting surface by a predetermined distanceand separated from the light source by a predetermined distance forinterpretation of the measurement of the reflected light.

[0493]FIGS. 59A through 59C illustrate positioning of contact devicesfor neurostimulation of tissues in the eye and brain.

[0494]FIG. 60 is a schematic illustration of a contact device having afixed frequency transmitter and power source for being tracked by anorbiting satellite.

[0495]FIG. 61 illustrates a contact device under an eyelid including apressure sensor incorporated in a circuit having a power source, an LEDdrive and an LED for production of an LED signal for remote activationof a device having a photodiode or optical receiver on a receptorscreen.

[0496]FIG. 62 is a cross-sectional view of a contact device having adrug delivery system incorporated therein.

[0497]FIG. 63 schematically illustrates a block diagram of an artificialpancreas system.

[0498]FIGS. 64A through 64D are schematic sectional illustrations ofexperiments performed on an eye.

[0499]FIGS. 65A through 65F shows a series of pictures related toin-vivo testing using fluorescein angiogram

[0500]FIGS. 66A through 66C are schematic illustrations of an in-vivoangiogram according to the biological principles of the invention.

[0501]FIG. 67A is an exemplary schematic of the blood vessels in theskin, non-fenestrated.

[0502]FIG. 67B is an exemplary schmatic of the blood vessels in theconjunctiva, fenestrated.

[0503]FIG. 68A shows a photomicrograph of the junction between skin andconjunctiva.

[0504]FIG. 68B shows a schematic illustration of a cross section of theeye showing the location of the microscopic structure depicted in FIG.68A and associated structure in the eye.

[0505]FIGS. 69A and 69B show schematic illustrations of the dimensionsand location of the conjunctiva.

[0506]FIG. 69C shows a schematic illustration of the vascularization ofthe conjunctiva and eye.

[0507]FIG. 69D is a photographic illustration of the palpebral andbulbar conjunctiva and blood vessels.

[0508]FIGS. 70A through 70C exemplary embodiments illustrating acontinuous feed-back system for non-invasive blood glucose monitoring.

[0509]FIG. 71 is a flow diagram showing the operational steps of thesystem depicted in FIGS. 70A-70C.

[0510]FIGS. 72A and 72B are exemplary embodiments of the intelligentcontact lens illustrating a complete microlaboratory of the currentinvention using microfluidics technology including power, control,processing and transmission systems.

[0511]FIGS. 73A through 73C are schematic illustrations of examples ofmicrofluidics systems according to the current invention.

[0512]FIGS. 74A through 74E are schematic illustrations of an exemplarybiosensor according to the principles of the current invention with theencircled area in FIG. 74A being shown on an enlarged scale in FIG. 74B.

[0513]FIGS. 75A through 75D are schematic illustrations of variousdesigns for chemical membrane biosensors according to the principles ofthe current invention.

[0514]FIG. 76 is a schematic illustration of an exemplary embodimentwith a dual system-in one single piece lens using both upper and lowereyelid pockets.

[0515]FIG. 77 is an exemplary embodiment in accordance with theprinciples of the invention.

[0516]FIGS. 78A through 78C are schematic illustrations of an exemplaryembodiment of dual system with two lenses using both upper and lowereyelid pockets with FIG. 78B being an enlarged view of the upper areaencircled in FIG. 78A and FIG. 78C being an enlarged view of the lowerarea encircled in FIG. 78A.

[0517]FIGS. 79A through 79C are schematic illustrations of exemplaryembodiments with transport enhancement capabilities.

[0518]FIG. 80 illustrates a microfluidic and bioelectronic chip systemin accordance with the present invention.

[0519]FIG. 81 is a schematic illustration of an integrated microfluidicsand electronics system in accordance with the present invention.

[0520]FIGS. 82A through 82D are schematic illustrations of an exemplaryembodiment for surgical implantation in the eye according to theprinciples of the current invention with FIG. 82C being an enlargedillustration of a portion of FIG. 82B.

[0521]FIG. 83 is a schematic illustration of an exemplary embodiment formeasurement of temperature and infectious agents according to theprinciples of the current invention.

[0522]FIG. 84 shows a schematic illustration of a dual system ICL with achemical sensing and a tracking device using global positioning systemtechnology.

[0523]FIG. 85 is a schematic block diagram of an apparatus according toone preferred embodiment of the present invention.

[0524]FIG. 86 is a schematic diagram of a sensor in accordance to apreferred embodiment of FIG. 85.

[0525]FIG. 87 is a schematic block diagram of an apparatus according toanother preferred embodiment of the present invention.

[0526]FIG. 88 is a schematic representation of the frontal view of thesurface of the eye

[0527] FIGS. 89A-D illustrates different positions for the location ofsensor of FIG. 87.

[0528]FIG. 90 is a schematic block diagram of an apparatus according toa preferred embodiment of the present invention.

[0529] FIGS. 91A-C illustrates various sensing arrangements inaccordance with the embodiment of FIG. 90.

[0530]FIG. 92 schematically illustrates a preferred embodiment inaccordance with the embodiment of FIG. 90.

[0531]FIG. 93A schematically illustrates an alternative embodiment forimplantation.

[0532]FIG. 93B is an enlarged view of the sensor arrangement shown inFIG. 93A.

[0533]FIG. 94 schematically illustrates another alternative embodimentof the present invention.

[0534]FIG. 95A schematically illustrates another embodiment of thepresent invention in cross-sectional view.

[0535]FIG. 95B is an enlarged view of the arrangement shown in FIG. 95A.

[0536]FIG. 96 schematically illustrates one preferred embodiment of thepresent invention.

[0537]FIG. 97A schematically illustrates one preferred embodiment of thepresent invention.

[0538]FIG. 97B is an enlarged view of the arrangement shown in FIG. 97A.

[0539]FIG. 97C schematically shows an alternative embodiment of thepresent invention.

[0540]FIG. 98A schematically illustrates a preferred embodiment forimplantation of the present invention.

[0541]FIG. 98B shows a cross-sectional view of the embodiment shown inFIG. 98A.

[0542] FIGS. 99A-D schematically illustrates implantable sensors inaccordance with an alternative embodiment of the present invention.

[0543]FIG. 100A schematically illustrates the position of sensor inaccordance with a preferred embodiment of the present invention.

[0544]FIG. 100B shows an enlarged view of the sensor shown in FIG.1100A.

[0545]FIG. 100C is a schematic block diagram of an apparatus accordingto one preferred embodiment of the present invention and shownschematically in FIGS. 100A-B.

[0546]FIG. 100D schematically illustrates a sensor arrangement inaccordance with a preferred embodiment of the present invention.

[0547]FIG. 101A is a schematic block diagram of an apparatus accordingto one preferred embodiment of the present invention.

[0548]FIG. 101B shows a cross-sectional view of one preferred embodimentof the present invention in accordance with the embodiment of FIG. 101A.

[0549] FIGS. 102A-B shows a cross-sectional view of one preferredembodiment of the present invention.

[0550]FIG. 102C shows a cross-sectional view of an alternativeembodiment of the present invention.

[0551]FIG. 103 schematically illustrates an alternative embodiment ofthe present invention.

[0552]FIG. 104A schematically illustrates a probe arrangement inaccordance with a preferred embodiment of the present invention.

[0553]FIG. 104B schematically illustrates a preferred embodiment of thepresent invention.

[0554] FIGS. 104B(1-3) schematically illustrate various positions fordirecting the probe arrangement in accordance with a preferredembodiment of the present invention.

[0555]FIG. 104C is a schematic block diagram for continuous monitoringof chemical substances in accordance with a preferred embodiment of thepresent invention.

[0556]FIG. 104D is a schematic block diagram of a probe arrangement FIG.104E schematically illustrates a probe arrangement in accordance with apreferred embodiment of the present invention.

[0557] FIGS. 104F-G shows cross-sectional views of the probe arrangementin two different positions in relation to the tissue being evaluated.

[0558] FIGS. 104H-J shows a frontal view of different arrangements forthe sensor and filter used in the measuring probe.

[0559] FIGS. 104K-1 shows a cross-sectional view of the probearrangement using a rotatable filter system in accordance with apreferred embodiment of the present invention.

[0560] FIGS. 104K-2 shows a frontal view of the rotatable filter ofFIGS. 104K-1.

[0561] FIGS. 104L-N schematically illustrates various measuringarrangements in accordance with an alternative embodiment of the presentinvention.

[0562]FIG. 104O schematically illustrates a probe arrangement with asupporting arm.

[0563]FIG. 104P schematically illustrates a probe arrangement forsimultaneous non-contact evaluation of both eyes for detection ofabnormalities due to asymmetric measurements.

[0564]FIG. 104Q, (1A), (1B), (2A), (2B), (3), (4) and (5) show a seriesof pictures related to in-vivo evaluation of radiation of theconjunctiva/plasma interface using infrared imaging.

[0565]FIG. 105A is a schematic simplified block diagram of one preferredembodiment of the present invention.

[0566]FIG. 105B shows a waveform corresponding to heart rhythm achievedby using a contact device and transducer placed on the eye.

[0567]FIG. 105C is a schematic block diagram of one preferred embodimentin accordance to FIG. 105B.

[0568]FIG. 105(D-1) shows a cross-sectional view of a heatingtransmission device adjacent to a neovascular membrane in the eyeaccording to a preferred embodiment of the invention.

[0569]FIG. 105(D-2) shows a side view of the heating transmissiondevice.

[0570]FIG. 105(D-3) shows a frontal view of the overheating transmissiondevice.

[0571] FIGS. 105(D-4 to D-6) schematically illustrates the surgicalimplantation of the device in FIG. 105(D-1).

[0572]FIG. 105(D-7) shows a frontal view of the overheating transmissiondevice in a cross-shape design.

[0573]FIG. 106A is a schematic illustration of a dispensation device inaccordance with a preferred embodiment of the present invention.

[0574]FIG. 106B is a schematic illustration of the preferred embodimentof FIG. 106A with an attached handle.

[0575] FIGS. 107A-B is a cross sectional view of the embodiment of FIGS.106A-B being actuated by the eyelid.

[0576]FIG. 108 is a cross-sectional view of an alternative embodimentshown in FIGS. 107A-B.

[0577]FIG. 109 is a cross sectional view of one preferred embodiment ofa dispensation device.

[0578] FIGS. 110A-B schematically illustrates an alternative embodimentfor the dispensation device.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Applanation

[0579] A preferred embodiment of the present invention will now bedescribed with reference to the drawings. According to the preferredembodiment illustrated in FIG. 1, a system is provided for measuringintraocular pressure by applanation. The system includes a contactdevice 2 for placement in contact with the cornea 4, and an actuationapparatus 6 for actuating the contact device 2 so that a portion thereofprojects inwardly against the cornea 4 to provide a predetermined amountof applanation. The system further includes a detecting arrangement 8for detecting when the predetermined amount of applanation of the cornea4 has been achieved and a calculation unit 10 responsive to thedetecting arrangement 8 for determining intraocular pressure based onthe amount of force the contact device 2 must apply against the cornea 4in order to achieve the predetermined amount of applanation.

[0580] The contact device 2 illustrated in FIG. 1 has an exaggeratedthickness to more clearly distinguish it from the cornea 4. FIGS. 2A-2Dmore accurately illustrate a preferred embodiment of the contact device2 which includes a substantially rigid annular member 12, a flexiblemembrane 14 and a movable central piece 16. The substantially rigidannular member 12 includes an inner concave surface 18 shaped to matchan outer surface of the cornea 4 and having a hole 20 defined therein.The substantially rigid annular member 12 has a maximum thickness(preferably approximately 1 millimeter) at the hole 20 and aprogressively decreasing thickness toward a periphery 21 of thesubstantially rigid annular member 12. The diameter of the rigid annularmember is approximately 11 millimeters and the diameter of the hole 20is approximately 5.1 millimeters according to a preferred embodiment.Preferably, the substantially rigid annular member 12 is made oftransparent polymethylmethacrylate; however, it is understood that manyother materials, such as glass and appropriately rigid plastics andpolymers, may be used to make the annular member 12. Preferably, thematerials are chosen so as not to interfere with light directed at thecornea or reflected back therefrom.

[0581] The flexible membrane 14 is preferably secured to the innerconcave surface 18 of the substantially rigid annular member 12 toprovide comfort for the wearer by preventing scratches or abrasions tothe corneal epithelial layer. The flexible membrane 14 is coextensivewith at least the hole 20 in the annular member 12 and includes at leastone transparent area 22. Preferably, the transparent area 22 spans theentire flexible membrane 14, and the flexible membrane 14 is coextensivewith the entire inner concave surface 18 of the rigid annular member 12.According to a preferred arrangement, only the periphery of the flexiblemembrane 14 and the periphery of the rigid annular member 12 are securedto one another. This tends to minimize any resistance the flexiblemembrane might exert against displacement of the movable central piece16 toward the cornea 4.

[0582] According to an alternative arrangement, the flexible membrane 14is coextensive with the rigid annular member and is heat-sealed theretoover its entire extent except for a circular region within approximatelyone millimeter of the hole 20.

[0583] Although the flexible membrane 14 preferably consists of a softand thin polymer, such as transparent silicone elastic, transparentsilicon rubber (used in conventional contact lens), transparent flexibleacrylic (used in conventional intraocular lenses), transparent hydrogel,or the like, it is well understood that other materials may be used inmanufacturing the flexible membrane 14.

[0584] The movable central piece 16 is slidably disposed within the hole20 and includes a substantially flat inner side 24 secured to theflexible membrane 14. The engagement of the inner side 24 to theflexible membrane 14 is preferably provided by glue or thermo-contacttechniques. It is understood, however, that various other techniques maybe used in order to securely engage the inner side 24 to the flexiblemembrane 14. Preferably, the movable central piece 16 has a diameter ofapproximately 5.0 millimeters and a thickness of approximately 1millimeter.

[0585] A substantially cylindrical wall 42 is defined circumferentiallyaround the hole 20 by virtue of the increased thickness of the rigidannular member 12 at the periphery of the hole 20. The movable centralpiece 16 is slidably disposed against this wall 42 in a piston-likemanner and preferably has a thickness which matches the height of thecylindrical wall 42. In use, the substantially flat inner side 24flattens a portion of the cornea 4 upon actuation of the movable centralpiece 16 by the actuation apparatus 6.

[0586] The overall dimensions of the substantially rigid annular member12, the flexible membrane 14 and the movable central piece 16 aredetermined by balancing several factors, including the desired range offorces applied to the cornea 4 during applanation, the discomforttolerances of the patients, the minimum desired area of applanation, andthe requisite stability of the contact device 2 on the cornea 4. Inaddition, the dimensions of the movable central piece 16 are preferablyselected so that relative rotation between the movable central piece 16and the substantially rigid annular member 12 is precluded, withouthampering the aforementioned piston-like sliding.

[0587] The materials used to manufacture the contact device 2 arepreferably selected so as to minimize any interference with lightincident upon the cornea 4 or reflected thereby.

[0588] Preferably, the actuation apparatus 6 illustrated in FIG. 1actuates the movable central piece 16 to cause sliding of the movablecentral piece 16 in the piston-like manner toward the cornea 4. In doingso, the movable central piece 16 and a central portion of the flexiblemembrane 14 are caused to project inwardly against the cornea 4. This isshown in FIGS. 2C and 2D. A portion of the cornea 4 is therebyflattened. Actuation continues until a predetermined amount ofapplanation is achieved.

[0589] Preferably, the movable central piece 16 includes a magneticallyresponsive element 26 arranged so as to slide along with the movablecentral piece 16 in response to a magnetic field, and the actuationapparatus 6 includes a mechanism 28 for applying a magnetic fieldthereto. Although it is understood that the mechanism 28 for applyingthe magnetic field may include a selectively positioned bar magnet,according to a preferred embodiment, the mechanism 28 for applying themagnetic field includes a coil 30 of long wire wound in a closely packedhelix and circuitry 32 for producing an electrical current through thecoil 30 in a progressively increasing manner. By progressivelyincreasing the current, the magnetic field is progressively increased.The magnetic repulsion between the actuation apparatus 6 and the movablecentral piece 16 therefore increases progressively, and this, in turn,causes a progressively greater force to be applied against the cornea 4until the predetermined amount of applanation is achieved.

[0590] Using known principles of physics, it is understood that theelectrical current passing through the coil 30 will be proportional tothe amount of force applied by the movable central piece 16 against thecornea 4 via the flexible membrane 14. Since the amount of forcerequired to achieve the predetermined amount of applanation isproportional to intraocular pressure, the amount of current required toachieve the predetermined amount of applanation will also beproportional to the intraocular pressure. Thus, a conversion factor forconverting a value of current to a value of intraocular pressure caneasily be determined experimentally upon dimensions of the system, themagnetic responsiveness of the magnetically responsive element 26,number of coil windings, and the like.

[0591] Besides using experimentation techniques, the conversion factormay also be determined using known techniques for calibrating atonometer. Such known techniques are based on a known relationship whichexists between the inward displacement of an indentation device and thevolume changes and pressure in the indented eye. Examples of suchtechniques are set forth in Shiotz, Communications: Tonometry, The Brit.J. of Ophthalmology, June 1920, p.249-266; Friedenwald, TonometerCalibration, Trans. Amer. Acad. of O. & O., January-February 1957, pp.108-126; and Moses, Theory and Calibration of the Schiotz Tonometer VII:Experimental Results of Tonometric Measurements: Scale Reading VersusIndentation Volume, Investigative Ophthalmology, September 1971, Vol.10, No. 9, pp. 716-723.

[0592] In light of the relationship between current and intraocularpressure, the calculation unit 10 includes a memory 33 for storing acurrent value indicative of the amount of current passing through thecoil 30 when the predetermined amount of applanation is achieved. Thecalculation unit 10 also includes a conversion unit 34 for convertingthe current value into an indication of intraocular pressure.

[0593] Preferably, the calculation unit 10 is responsive to thedetecting arrangement 8 so that when the predetermined amount ofapplanation is achieved, the current value (corresponding to the amountof current flowing through the coil 30) is immediately stored in thememory 33. At the same time, the calculation unit 10 produces an outputsignal directing the current producing circuitry 32 to terminate theflow of current. This, in turn, terminates the force against the cornea4. In an alternative embodiment, the current producing circuitry 32could be made directly responsive to the detecting arrangement 8 (i.e.,not through the calculation unit 10) so as to automatically terminatethe flow of current through the coil 30 upon achieving the predeterminedamount of applanation.

[0594] The current producing circuitry 32 may constitute anyappropriately arranged circuit for achieving the progressivelyincreasing current. However, a preferred current producing circuit 32includes a switch and a DC power supply, the combination of which iscapable of producing a step function. The preferred current producingcircuitry 32 further comprises an integrating amplifier which integratesthe step function to produce the progressively increasing current.

[0595] The magnetically responsive element 26 is circumferentiallysurrounded by a transparent peripheral portion 36. The transparentperipheral portion 36 is aligned with the transparent area 22 andpermits light to pass through the contact device 2 to the cornea 4 andalso permits light to reflect from the cornea 4 back out of the contactdevice 2 through the transparent on peripheral portion 36. Although thetransparent peripheral portion 36 may consist entirely of an air gap,for reasons of accuracy and to provide smoother sliding of the movablecentral piece 16 through the rigid annular member 12, it is preferredthat a transparent solid material constitute the transparent peripheralportion 36. Exemplary transparent solid materials include polymethylmethacrylate, glass, hard acrylic, plastic polymers, and the like.

[0596] The magnetically responsive element 26 preferably comprises anannular magnet having a central sight hole 38 through which a patient isable to see while the contact device 2 is located on the patient'scornea 4. The central sight hole 38 is aligned with the transparent area22 of the flexible membrane 14 and is preferably at least 1-2millimeters in diameter.

[0597] Although the preferred embodiment includes an annular magnet asthe magnetically responsive element 26, it is understood that variousother magnetically responsive elements 26 may be used, including variousferromagnetic materials and/or suspensions of magnetically responsiveparticles in liquid. The magnetically responsive element 26 may alsoconsist of a plurality of small bar magnets arranged in a circle, tothereby define an opening equivalent to the illustrated central sighthole 38. A transparent magnet may also be used.

[0598] A display 40 is preferably provided for numerically displayingthe intraocular pressure detected by the system. The display 40preferably comprises a liquid crystal display (LCD) or light emittingdiode (LED) display connected and responsive to the conversion unit 34of the calculation unit 10.

[0599] Alternatively, the display 40 can be arranged so as to giveindications of whether the intraocular pressure is within certainranges. In this regard, the display 40 may include a green LED 40A, ayellow LED 40B, and a red LED 40C. When the pressure is within apredetermined high range, the red LED 40C is illuminated to indicatethat medical attention is needed. When the intraocular pressure iswithin a normal range, the green LED 40A is illuminated. The yellow LED40B is illuminated when the pressure is between the normal range and thehigh range to indicate that the pressure is somewhat elevated and that,although medical attention is not currently needed, careful and frequentmonitoring is recommended.

[0600] Preferably, since different patients may have differentsensitivities or reactions to the same intraocular pressure, the rangescorresponding to each LED 40A,40B,40C are calibrated for each patient byan attending physician. This way, patients who are more susceptible toconsequences from increased intraocular pressure may be alerted to seekmedical attention at a pressure less than the pressure at which otherless-susceptible patients are alerted to take the same action. The rangecalibrations may be made using any known calibration device 40Dincluding variable gain amplifiers or voltage divider networks withvariable resistances.

[0601] The detecting arrangement 8 preferably comprises an opticaldetection system including two primary beam emitters 44,46; two lightsensors 48,50; and two converging lenses 52,54. Any of a plurality ofcommercially available beam emitters may be used as emitters 44,46,including low-power laser beam emitting devices and infra-red (IR) beamemitting devices. Preferably, the device 2 and the primary beam emitters44,46 are arranged with respect to one another so that each of theprimary beam emitters 44,46 emits a primary beam of light toward thecornea through the transparent area 22 of the device and so that theprimary beam of light is reflected back through the device 2 by thecornea 4 to thereby produce reflected beams 60,62 of light with adirection of propagation dependent upon the amount of applanation of thecornea. The two light sensors 48,50 and two converging lenses 52,54 arepreferably arranged so as to be aligned with the reflected beams 60,62of light only when the predetermined amount of applanation of the cornea4 has been achieved. Preferably, the primary beams 56,58 pass throughthe substantially transparent peripheral portion 36.

[0602] Although FIG. 1 shows the reflected beams 60,62 of lightdiverging away from one another and well away from the two converginglenses 52,54 and light sensors 48,50, it is understood that as thecornea 4 becomes applanated the reflected beams 60,62 will approach thetwo light sensors 48,50 and the two converging lenses 52,54. When thepredetermined amount of applanation is achieved, the reflected beams60,62 will be directly aligned with the converging lenses 52,54 and thesensors 48,50. The sensors 48,50 are therefore able to detect when thepredetermined amount of applanation is achieved by merely detecting thepresence of the reflected beams 60,62. Preferably, the predeterminedamount of applanation is deemed to exist when all of the sensors 48,50receive a respective one of the reflected beams 60,62.

[0603] Although the illustrated arrangement is generally effective usingtwo primary beam emitters 44,46 and two light sensors 48,50, betteraccuracy can be achieved in patients with astigmatisms by providing fourbeam emitters and four light sensors arranged orthogonally with respectto one another about the longitudinal axis of the actuation apparatus 6.As in the case with two beam emitters 44,46 and light sensors 48,50, thepredetermined amount of applanation is preferably deemed to exist whenall of the sensors receive a respective one of the reflected beams.

[0604] A sighting arrangement is preferably provided for indicating whenthe actuation apparatus 6 and the detecting arrangement 8 are properlyaligned with the device 2. Preferably, the sighting arrangement includesthe central sight hole 38 in the movable central piece 16 through whicha patient is able to see while the device 2 is located on the patient'scornea 4. The central sight hole 38 is aligned with the transparent area22. In addition, the actuation apparatus 6 includes a tubular housing 64having a first end 66 for placement over an eye equipped with the device2 and a second opposite end 68 having at least one mark 70 arranged suchthat, when the patient looks through the central sight hole 38 at themark 70, the device 2 is properly aligned with the actuation apparatus 6and detecting arrangement 8.

[0605] Preferably, the second end 68 includes an internal mirror surface72 and the mark 70 generally comprises a set of cross-hairs. FIG. 3illustrates the view seen by a patient through the central sight hole 38when the device 2 is properly aligned with the actuation apparatus 6 anddetecting arrangement 8. When proper alignment is achieved, thereflected image 74 of the central sight hole 38 appears in the mirrorsurface 72 at the intersection of the two cross-hairs which constitutethe mark 70. (The size of the image 74 is exaggerated in FIG. 3 to moreclearly distinguish it from other elements in the drawing).

[0606] Preferably, at least one light 75 is provided inside the tubularhousing 64 to illuminate the inside of the housing 64 and facilitatevisualization of the cross-hairs and the reflected image 74. Preferably,the internal mirror surface 72 acts as a mirror only when the light 75is on, and becomes mostly transparent upon deactivation of the light 75due to darkness inside the tubular housing 64. To that end, the secondend 68 of the tubular housing 68 maybe manufactured using “one-wayglass” which is often found in security and surveillance equipment.

[0607] Alternatively, if the device is to be used primarily byphysicians, optometrists, or the like, the second end 68 may be merelytransparent. If, on the other hand, the device is to be used by patientsfor self-monitoring, it is understood that the second end 68 may merelyinclude a mirror.

[0608] The system also preferably includes an optical distance measuringmechanism for indicating whether the device 2 is spaced at a properaxial distance from the actuation apparatus 6 and the detectingarrangement 8. The optical distance measurement mechanism is preferablyused in conjunction with the sighting arrangement.

[0609] Preferably, the optical distance measuring mechanism includes adistance measurement beam emitter 76 for emitting an optical distancemeasurement beam 78 toward the device 2. The device 2 is capable ofreflecting the distance measurement beam 78 to produce a first reflecteddistance measurement beam 80. Arranged in the path of the firstreflected distance measurement beam 80 is a preferably convex mirror 82.The convex mirror 82 reflects the first reflected distance measurementbeam 80 to create a second reflected distance measurement beam 84 andserves to amplify any variations in the first reflected beam's directionof propagation. The second reflected distance measurement beam 84 isdirected generally toward a distance measurement beam detector 86. Thedistance measurement beam detector 86 is arranged so that the secondreflected distance measurement beam 84 strikes a predetermined portionof the distance measurement beam detector 86 only when the device 2 islocated at the proper axial distance from the actuation apparatus 6 andthe detecting arrangement 8. When the proper axial distance is lacking,the second reflected distance measurement beam strikes another portionof the beam detector 86.

[0610] An indicator 88, such as an LCD or LED display, is preferablyconnected and responsive to the beam detector 86 for indicating that theproper axial distance has been achieved only when the reflected distancemeasurement beam strikes the predetermined portion of the distancemeasurement beam detector.

[0611] Preferably, as illustrated in FIG. 1, the distance measurementbeam detector 86 includes a multi-filter optical element 90 arranged soas to receive the second reflected distance measurement beam 84. Themulti-filter optical element 90 contains a plurality of optical filters92. Each of the optical filters 92 filters out a different percentage oflight, with the predetermined portion of the detector 86 being definedby a particular one of the optical filters 92 and a filtering percentageassociated therewith.

[0612] The distance measurement beam detector 86 further includes a beamintensity detection sensor 94 for detecting the intensity of the secondreflected distance measurement beam 84 after the beam 84 passes throughthe multi-filter optical element 90. Since the multi-filter opticalelement causes this intensity to vary with axial distance, the intensityis indicative of whether the device 2 is at the proper distance from theactuation apparatus 6 and the detecting arrangement 8.

[0613] A converging lens 96 is preferably located between themulti-filter optical element 90 and the beam intensity detection sensor94, for focussing the second reflected distance measurement beam 84 onthe beam intensity detection sensor 94 after the beam 84 passes throughthe multi-filter optical element 90.

[0614] Preferably, the indicator 88 is responsive to the beam intensitydetection sensor 94 so as to indicate what corrective action should betaken, when the device 2 is not at the proper axial distance from theactuation apparatus 6 and the detecting arrangement 8, in order toachieve the proper distance. The indication given by the indicator 88 isbased on the intensity and which of the plurality of optical filters 92achieves the particular intensity by virtue of a filtering percentageassociated therewith.

[0615] For example, when the device 2 is excessively far from theactuation apparatus 6, the second reflected distance measurement beam 84passes through a dark one of the filters 92. There is consequently areduction in beam intensity which causes the beam intensity detectionsensor 94 to drive the indicator 88 with a signal indicative of the needto bring the device 2 closer to the actuation apparatus. The indicator88 responds to this signal by communicating the need to a user of thesystem.

[0616] Alternatively, the signal indicative of the need to bring thedevice 2 closer to the actuation apparatus can be applied to a computerwhich performs corrections automatically.

[0617] In like manner, when the device 2 is excessively close to theactuation apparatus 6, the second reflected distance measurement beam 84passes through a lighter one of the filters 92. There is consequently anincrease in beam intensity which causes the beam intensity detectionsensor 94 to drive the indicator 88 with a signal indicative of the needto move the device 2 farther from the actuation apparatus. The indicator88 responds to this signal by communicating the need to a user of thesystem.

[0618] In addition, computer-controlled movement of the actuationapparatus farther away from the device 2 may be achieved automaticallyby providing an appropriate computer-controlled moving mechanismresponsive to the signal indicative of the need to move the device 2farther from the actuation apparatus.

[0619] With reference to FIG. 3, the indicator 88 preferably comprisesthree LEDs arranged in a horizontal line across the second end 68 of thehousing 64. When illuminated, the left LED 88 a, which is preferablyyellow, indicates that the contact device 2 is too far from theactuation apparatus 6 and the detecting arrangement 8. Similarly, whenilluminated, the right LED 88 b, which is preferably red, indicates thatthe contact device 2 is too close to the actuation apparatus 6 and thedetecting arrangement 8. When the proper distance is achieved, thecentral LED 88 c is illuminated. Preferably, the central LED 88 c isgreen. The LEDs 88 a-88 c are selectively illuminated by the beamintensity detection sensor 94 in response to the beam's intensity.

[0620] Although FIG. 1 illustrates an arrangement of filters 92 whereina reduction in intensity signifies a need to move the device closer, itis understood that the present invention is not limited to such anarrangement. The multi-filter optical element 90, for example, may bereversed so that the darkest of the filters 92 is positioned adjacentthe end 68 of the tubular housing 64. When such an arrangement is used,an increase in beam intensity would signify a need to move the device 2farther away from the actuation apparatus 6.

[0621] Preferably, the actuation apparatus 6 (or at least the coil 30thereof) is slidably mounted within the housing 64 and a knob andgearing (e.g., rack and pinion) mechanism are provided for selectivelymoving the actuation apparatus 6 (or coil 30 thereof) axially throughthe housing 64 in a perfectly linear manner until the appropriate axialdistance from the contact device 2 is achieved. When such an arrangementis provided, the first end 66 of the housing 64 serves as a positioningmechanism for the contact device 2 against which the patient presses thefacial area surrounding eye to be examined. once the facial area restsagainst the first end 66, the knob and gearing mechanism are manipulatedto place the actuation apparatus 6 (or coil 30 thereof) at the properaxial distance from the contact device 2.

[0622] Although facial contact with the first end 66 enhances stability,it is understood that facial contact is not an essential step inutilizing the present invention.

[0623] The system also preferably includes an optical alignmentmechanism for indicating whether the device 2 is properly aligned withthe actuation apparatus 6 and the detecting arrangement 8. The opticalalignment mechanism includes two alignment beam detectors 48′,50′ forrespectively detecting the reflected beams 60,62 of light prior to anyapplanation. The alignment beam detectors 48′,50′ are arranged so thatthe reflected beams 60,62 of light respectively strike a predeterminedportion of the alignment beam detectors 48′,50′ prior to applanationonly when the device 2 is properly aligned with respect to the actuationapparatus 6 and the detecting arrangement 8. When the device 2 is notproperly aligned, the reflected beams 60,62 strike another portion ofthe alignment beam detectors 48′,50′, as will be described hereinafter.

[0624] The optical alignment mechanism further includes an indicatorarrangement responsive to the alignment beam detectors 48′,50′. Theindicator arrangement preferably includes a set of LEDs 98,100,102,104which indicate that the proper alignment has been achieved only when thereflected beams 60,62 of light respectively strike the predeterminedportion of the alignment beam detectors 48′,50′ prior to applanation.

[0625] Preferably, each of the alignment beam detectors 48′,50′ includesa respective multi-filter optical element 106,108. The multi-filteroptical elements 106,108 are arranged so as to receive the reflectedbeams 60,62 of light. Each multi-filter optical element 106,108 containsa plurality of optical filters 110 ₁₀-110 ₉₀ (FIGS. 4 and 5), each ofwhich filters out a different percentage of light. In FIGS. 4 and 5, thedifferent percentages are labeled between 10 and 90 percent inincrements of ten percent. It is understood, however, that many otherarrangements and increments will suffice.

[0626] For the illustrated arrangement, it is preferred that thecentrally located filters 110 ₅₀ which filter out 50% of the lightrepresent the predetermined portion of each alignment beam detector48′,50′. Proper alignment is therefore deemed to exist when thereflected beams 60,62 of light pass through the filters 110 ₅₀ and theintensity of the beams 60,62 is reduced by 50%.

[0627] Each of the alignment beam detectors 48′,50′ also preferablyincludes a beam intensity detector 112,114 for respectively detectingthe intensity of the reflected beams 60,62 of light after the reflectedbeams 60,62 of light pass through the multi-filter optical elements106,108. The intensity of each beam is indicative of whether the device2 is properly aligned with respect to the actuation apparatus 6 and thedetecting arrangement.

[0628] A converging lens 116,118 is preferably located between eachmulti-filter optical element 106,108 and its respective beam intensitydetector 112,114. The converging lens 116,118 focusses the reflectedbeams 60,62 of light onto the beam intensity detectors 112,114 after thereflected beams 60,62 pass through the multi-filter optical elements106,108.

[0629] Each of the beam intensity detectors 112,114 has its outputconnected to an alignment beam detection circuit which, based on therespective outputs from the beam intensity detectors 112,114, determineswhether there is proper alignment, and if not, drives the appropriateone or ones of the LEDs 98,100,102,104 to indicate the corrective actionwhich should be taken.

[0630] As illustrated in FIG. 3, the LEDs 98,100,102,104 arerespectively arranged above, to the right of, below, and to the left ofthe intersection of the cross-hairs 70. No LEDs 98,100,102,104 areilluminated unless there is a misalignment. Therefore, a lack ofillumination indicates that the device 2 is properly aligned with theactuation apparatus 6 and the detecting arrangement 8.

[0631] When the device 2 on the cornea 4 is too high, the beams 56,58 oflight strike a lower portion of the cornea 4 and because of the cornea'scurvature, are reflected in a more downwardly direction. The reflectedbeams 60,62 therefore impinge on the lower half of the multi-filterelements 106,108, and the intensity of each reflected beam 60,62 isreduced by no more than 30%. The respective intensity reductions arethen communicated to the alignment detection circuit 120 by the beamintensity detectors 112,114. The alignment detection circuit 120interprets this reduction of intensity to result from a misalignmentwherein the device 2 is too high. The alignment detection circuit 120therefore causes the upper LED 98 to illuminate. Such illuminationindicates to the user that the device 2 is too high and must be loweredwith respect to the actuation apparatus 6 and the detecting arrangement8.

[0632] Similarly, when the device 2 on the cornea 4 is too low, thebeams 56,58 of light strike an upper portion of the cornea 4 and becauseof the cornea's curvature, are reflected in a more upwardly direction.The reflected beams 60,62 therefore impinge on the upper half of themulti-filter elements 106,108, and the intensity of each reflected beam60,62 is reduced by at least 70%. The respective intensity reductionsare then communicated to the alignment detection circuit 120 by the beamintensity detectors 112,114. The alignment detection circuit 120interprets this particular reduction of intensity to result from amisalignment wherein the device 2 is too low. The alignment detectioncircuit 120 therefore causes the lower LED 102 to illuminate. Suchillumination indicates to the user that the device 2 is too low and mustbe raised with respect to t he actuation apparatus 6 and the detectingarrangement 8.

[0633] With reference to FIG. 1, when the device 2 is too far to theright, the beams 56,58 strike a more leftward side of the cornea 4 andbecause of the cornea's curvature, are reflected in a more leftwarddirection. The reflected beams 60,62 therefore impinge on the lefthalves of the multi-filter elements 106,108. Since the filteringpercentages decrease from left to right in multi-filter element 106 andincrease from left to right in multifilter element 108, there will be adifference in the intensities detected by the beam intensity detectors112,114. In particular, the beam intensity detector 112 will detect lessintensity than the beam intensity detector 114. The differentintensities are then communicated to the alignment detection circuit 120by the beam intensity detectors 112,114. The alignment detection circuit120 interprets the intensity difference wherein the intensity at thebeam intensity detector 114 is higher than that at the beam intensitydetector 112, to result from a misalignment wherein the device 2 is toofar to the right in FIG. 1 (too far to the left in FIG. 3). Thealignment detection circuit 120 therefore causes the left LED 104 toilluminate. Such illumination indicates to the user that the device 2 istoo far to the left (in FIG. 3) and must be moved to the right (left inFIG. 1) with respect to the actuation apparatus 6 and the detectingarrangement 8.

[0634] Similarly, when the device 2 in FIG. 1 is too far to the left,the beams 56,58 strike a more rightward side of the cornea 4 and becauseof the cornea's curvature, are reflected in a more rightwardlydirection. The reflected beams 60,62 therefore impinge on the righthalves of the multi-filter elements 106,108. Since the filteringpercentages decrease from left to right in multi-filter element 106 andincrease from left to right in multifilter element 108, there will be adifference in the intensities detected by the beam intensity detectors112,114. In particular, the beam intensity detector 112 will detect moreintensity than the beam intensity detector 114. The differentintensities are then communicated to the alignment detection circuit 120by the beam intensity detectors 112,114. The alignment detection circuit120 interprets the intensity difference wherein the intensity at thebeam intensity detector 114 is lower than that at the beam intensitydetector 112, to result from a misalignment wherein the device 2 is toofar to the left in FIG. 1 (too far to the right in FIG. 3). Thealignment detection circuit 120 therefore causes the right LED 100 toilluminate. Such illumination indicates to the user that the device 2 istoo far to the right (in FIG. 3) and must be moved to the left (right inFIG. 1) with respect to the actuation apparatus 6 and the detectingarrangement 8.

[0635] The combination of LEDs 98,100,102,104 and the alignmentdetection circuit 120 therefore constitutes a display arrangement whichis responsive to the beam intensity detectors 112,114 and whichindicates what corrective action should be taken, when the device 2 isnot properly aligned, in order to achieve proper alignment. Preferably,the substantially transparent peripheral portion 36 of the movablecentral piece 16 is wide enough to permit passage of the beams 56,58 tothe cornea 4 even during misalignment.

[0636] It is understood that automatic alignment correction maybeprovided via computer-controlled movement of the actuation apparatusupwardly, downwardly, to the right, and/or to the left, whichcomputer-controlled movement may be generated by an appropriatecomputer-controlled moving mechanism responsive to the optical alignmentmechanism.

[0637] The optical alignment mechanism is preferably used in conjunctionwith the sighting arrangement, so that the optical alignment mechanismmerely provides indications of minor alignment corrections while thesighting arrangement provides an indication of major alignmentcorrections. It is understood, however, that the optical alignmentmechanism can be used in lieu of the sighting mechanism if thesubstantially transparent peripheral portion 36 is made wide enough.

[0638] Although the foregoing alignment mechanism uses the samereflected beams 60,62 used by the detecting arrangement 8, it isunderstood that separate alignment beam emitters may be used in order toprovide separate and distinct alignment beams. The foregoing arrangementis preferred because it saves the need to provide additional emittersand thus is less expensive to manufacture.

[0639] Nevertheless, optional alignment beam emitters 122,124 areillustrated in FIG. 1. The alignment mechanism using these optionalalignment beam emitters 122,124 would operate in essentially the samemanner as its counterpart which uses the reflected beams 60,62.

[0640] In particular, each of the alignment beam emitters 122,124 emitsan optical alignment beam toward the device 2. The alignment beam isreflected by the cornea 4 to produce a reflected alignment beam. Thealignment beam detectors 48′,50′ are arranged so as to receive, not thereflected beams 60,62 of light, but rather the reflected alignment beamswhen the alignment beam emitters 122,124 are present. More specifically,the reflected alignment beams strike a predetermined portion of eachalignment beam detector 48′,50′ prior to applanation only when thedevice 2 is properly aligned with respect to the actuation apparatus 6and the detecting arrangement 8. The rest of the system preferablyincludes the same components and operates in the same manner as thesystem which does not use the optional. alignment beam emitters 122,124.

[0641] The system may further include an applicator for gently placingthe contact device 2 on the cornea 4. As illustrated in FIGS. 5A-5F, apreferred embodiment of the applicator 127 includes an annular piece127A at the tip of the applicator 127. The annular piece 127A matchesthe shape of the movable central piece 16. Preferably, the applicator127 also includes a conduit 127CN having an open end which opens towardthe annular piece 127A. An opposite end of the conduit 127CN isconnected to a squeeze bulb 127SB. The squeeze bulb 127SB includes aone-way valve 127V which permits the flow of air into the squeeze bulb127SB, but prevents the flow of air out of the squeeze bulb 127SBthrough the valve 127V. When the squeeze bulb 127SB is squeezed and thenreleased, a suction effect is created at the open end of the conduit127CN as the squeeze bulb 127SB tries to expand to its pre-squeezeshape. This suction effect may be used to retain the contact device 2 atthe tip of the applicator 127.

[0642] In addition, a pivoted lever system 127B is arranged to detachthe movable central piece 16 from the annular piece 127A when a knob127C at the base of the applicator 127 is pressed, thereby nudging thecontact device 2 away from the annular piece 127A.

[0643] Alternatively, the tip of the applicator 127 may be selectivelymagnetized and demagnetized using electric current flowing through theannular piece 127A. This arrangement replaces the pivoted lever system127B with a magnetization mechanism capable of providing a magneticfield which repels the movable central piece 16, thereby applying thecontact device 2 to the cornea 4.

[0644] A preferred circuit arrangement for implementing the abovecombination of elements is illustrated schematically in FIG. 6.According to the preferred circuit arrangement, the beam intensitydetectors' 112,114 comprise a pair of photosensors which provide avoltage output proportional to the detected beam intensity. The outputfrom each beam intensity detector 112,114 is respectively connected tothe non-inverting input terminal of a filtering amplifier 126,128. Theinverting terminals of the filtering amplifiers 126,128 are connected toground. The amplifiers 126,128 therefore provide a filtering andamplification effect.

[0645] In order to determine whether proper vertical alignment exists,the output from the filtering amplifier 128 is applied to an invertinginput terminal of a vertical alignment comparator 130. The verticalalignment comparator 130 has its non-inverting input terminal connectedto a reference voltage Vref₁. The reference voltage Vref₁ is selected sothat it approximates the output from the filtering amplifier 128whenever the light beam 62 strikes the central row of filters 1104040 ofthe multi-filter optical element 108 (i.e., when the proper verticalalignment is achieved).

[0646] Consequently, the output from the comparator 130 is approximatelyzero when proper vertical alignment is achieved, is significantlynegative when the contact device 2 is too high, and is significantlypositive when the contact device 2 is too low. This output from thecomparator 130 is then applied to a vertical alignment switch 132. Thevertical alignment switch 132 is logically arranged to provide apositive voltage to an AND-gate 134 only when the output from thecomparator 130 is approximately zero, to provide a positive voltage tothe LED 98 only when the output from the comparator 130 is negative, andto provide a positive voltage to the LED 102 only when the output fromthe comparator 130 is positive. The LEDs 98,102 are thereby illuminatedonly when there is a vertical misalignment and each illumination clearlyindicates what corrective action should to be taken.

[0647] In order to determine whether proper horizontal alignment exists,the output from the filtering amplifier 126 is applied to anon-invertinginput terminal of a horizontal alignment comparator 136, while theinverting input terminal of the horizontal alignment comparator 136 isconnected to the output from the filtering amplifier 128. The comparator136 therefore produces an output which is proportional to the differencebetween the intensities detected by the beam intensity detectors112,114. This difference is zero whenever the light beams 60,62 strikethe central column of filters 110 ₂₀, 110 ₅₀, 110 ₈₀ of the multi-filteroptical elements 106,108 (i.e., when the proper horizontal alignment isachieved).

[0648] The output from the comparator 136 is therefore zero when theproper horizontal alignment is achieved, is negative when the contactdevice 2 is too far to the right (in FIG. 1), and is positive when thecontact device 2 is too far to the left (in FIG. 1). This output fromthe comparator 130 is then applied to a horizontal alignment switch 138.The horizontal alignment switch 138 is logically arranged to provide apositive voltage to the AND-gate 134 only when the output from thecomparator 136 is zero, to provide a positive voltage to the LED 104only when the output from the comparator 136 is negative, and to providea positive voltage to the LED 100 only when the output from thecomparator 136 is positive. The LEDs 100, 104 are thereby illuminatedonly when there is a horizontal misalignment and each illuminationclearly indicates what corrective action should be taken.

[0649] In accordance with the preferred circuit arrangement illustratedin FIG. 6, the beam intensity detection sensor 94 of the distancemeasurement beam detector 86 includes a photosensor 140 which produces avoltage output proportional to the detected beam intensity. This voltageoutput is applied to the non-inverting input terminal of a filteringamplifier 142. The inverting terminal of the filtering amplifier 142 isconnected to ground. Accordingly, the filtering amplifier 142 filtersand amplifies the voltage output from the photosensor 140. The outputfrom the filtering amplifier 142 is applied to the non-inverting inputterminal of a distance measurement comparator 144. The comparator 144has its inverting terminal connected to a reference voltage Vref₂.Preferably, the reference voltage Vref₂ is selected so as to equal theoutput of the filtering amplifier 142 only when the proper axialdistance separates the contact device 2 from the actuation apparatus 6and detecting arrangement 8.

[0650] Consequently, the output from the comparator 144 is zero wheneverthe proper axial distance is achieved, is negative whenever the secondreflected beam 84 passes through a dark portion of the multi-filteroptical element 90 (i.e., whenever the axial distance is too great), andis positive whenever the second reflected beam 84 passes through a lightportion of the multifilter optical element 90 (i.e., whenever the axialdistance is too short).

[0651] The output from the comparator 144 is then applied to a distancemeasurement switch 146. The distance measurement switch 146 drives theLED 88 c with positive voltage whenever the output from the comparator144 is zero, drives the LED 88 b only when the output from thecomparator 144 is positive, and drives the LED 88 a only when the outputfrom the comparator 144 is negative. The LEDs 88 a,88 b are therebyilluminated only when the axial distance separating the contact device 2from the actuation apparatus 6 and the detecting arrangement 8 isimproper. Each illumination clearly indicates what corrective actionshould be taken. Of course, when the LED 88 c is illuminated, nocorrective action is necessary.

[0652] With regard to the detecting arrangement 8, the preferred circuitarrangement illustrated in FIG. 6 includes the two light sensors 48,50.The outputs from the light-sensors 48,50 are applied to and added by anadder 147. The output from the adder 147 is then applied to thenon-inverting input terminal of a filtering amplifier 148. The invertinginput terminal of the same amplifier 148 is connected to ground. As aresult, the filtering amplifier 148 filters and amplifies the sum of theoutput voltages from the light sensor 48,50. The output from thefiltering amplifier 148 is then applied to the non-inverting inputterminal of an applanation comparator 150. The inverting input terminalof the applanation comparator 150 is connected to a reference voltageVref₃. Preferably, the reference voltage Vref₃ is selected so as toequal the output from the filtering amplifier 148 only when thepredetermined amount of applanation is achieved (i.e., when thereflected beams 60,62 strike the light sensors 48,50). The output fromthe applanation comparator 150 therefore remains negative until thepredetermined amount of applanation is achieved.

[0653] The output from the applanation comparator 150 is connected to anapplanation switch 152. Th applanation switch 152 provides a positiveoutput voltage when the output from the applanation comparator 150 isnegative and terminates its positive output voltage whenever the outputfrom the applanation comparator 150 becomes positive.

[0654] Preferably, the output from the applanation switch 152 isconnected to an applanation speaker 154 which audibly indicates when thepredetermined amount of applanation has been achieved. In particular,the speaker 154 is activated whenever the positive output voltage fromthe applanation, switch 152 initially disappears.

[0655] In the preferred circuit of FIG. 6, the coil 30 is electricallyconnected to the current producing circuitry 32 which, in turn, includesa signal generator capable of producing the progressively increasingcurrent in the coil 30. The current producing circuitry 32 is controlledby a start/stop switch 156 which is selectively activated anddeactivated by an AND-gate 158.

[0656] The AND-gate 158 has two inputs, both of which must exhibitpositive voltages in order to activate the start/stop switch 156 andcurrent producing circuitry 32. A first input 160 of the two inputs isthe output from the applanation switch 152. Since the applanation switch152 normally has a positive output voltage, the first input 160 remainspositive and the AND-gate is enabled at least with respect to the firstinput 160. However, whenever the predetermined amount of applanation isachieved (i.e. whenever the positive output voltage is no longer presentat the output from the applanation switch 152), the AND-gate 158deactivates the current producing circuitry 32 via the start/stop switch156.

[0657] The second input to the AND-gate 158 is the output from anotherAND-gate 162. The other AND-gate 162 provides a positive output voltageonly when a push-action switch 164 is pressed and only when the contactdevice 2 is located at the proper axial distance from, and is properlyaligned both vertically and horizontally with, the actuation apparatus 6and the detecting arrangement 8. The current producing circuitry 32therefore cannot be activated unless there is proper alignment and theproper axial distance has been achieved. In order to achieve suchoperation, the output from the AND-gate 134 is connected to a firstinput of the AND-gate 162 and the push-action switch 164 is connected tothe second input of the AND-gate 162.

[0658] A delay element 163 is located electrically between the AND-gate134 and the AND-gate 162. The delay element 163 maintains a positivevoltage at the first input terminal to the AND-gate 162 for apredetermined period of time after a positive voltage first appears atthe output terminal of the AND-gate 134. The primary purpose of thedelay element 163 is to prevent deactivation of the current producingcircuitry 32 which would otherwise occur in response to changes in thepropagation direction of the reflected beams 60,62 during the initialstages of applanation. The predetermined period of time is preferablyselected pursuant to the maximum amount of time that it could take toachieve the predetermined amount of applanation.

[0659] According to the preferred circuitry illustrated in FIG. 6,misalignment and improper axial separation of the contact device 2 withrespect to the actuation apparatus 6 and detecting arrangement 8 isaudibly announced by a speaker 166 and causes deactivation of a display167. The display 167 and speaker 166 are connected and responsive to anAND-gate 168. The AND-gate 168 has an inverting input connected to thepush-action switch 164 and another input connected to a three-inputOR-gate 170.

[0660] Therefore, when the push-action switch 164 is activated, theinverting input terminal of the AND-gate 168 prevents a positive voltagefrom appearing at the output from the AND-gate 168. Activation of thespeaker 166 is thereby precluded. However, when the push-action switchis not activated, any positive voltage at any of the three inputs to theOR-gate 170 will activate the speaker 166. The three inputs to theOR-gate 170 are respectively connected to outputs from three otherOR-gates 172,174,176. The OR-gates 172,174,176, in turn, have theirinputs respectively connected to the LEDs 100,104, LEDs 98,102, and LEDs88 a,88 b. Therefore, whenever anyone of these LEDs 88 a, 88 b, 98, 100,102, 104 is activated, the OR-gate 170 produces a positive outputvoltage. The speaker 166, as a result, will be activated whenever anyone of the LEDs 88 a,88 b,98,100,102,104 is activated while thepush-action switch 164 remains deactivated.

[0661] Turning now to the current producing circuitry 32, the outputfrom the current producing circuitry 32 is connected to the coil 30. Thecoil 30, in turn, is connected to a current-to-voltage transducer 178.The output voltage from the current-to-voltage transducer 178 isproportional to the current flowing through the coil 30 and is appliedto the calculation unit 10.

[0662] The calculation unit 10 receives the output voltage from thetransducer 178 and converts this output voltage indicative of current toan output voltage indicative of intraocular pressure. Initially, anoutput voltage from the filtering amplifier 142 indicative of the axialdistance separating the contact device 2 from the actuation apparatus 6and the detecting arrangement 8, is multiplied by a reference voltageVref₄ using a multiplier 180. The reference voltage Vref₄ represents adistance calibration constant. The output from the multiplier 180 isthen squared by a multiplier 182 to create an output voltage indicativeof distance squared (d²).

[0663] The output from the multiplier 182 is then supplied to an inputterminal of a divider 184. The other input terminal of the divider 184receives the output voltage indicative of current from thecurrent-to-voltage transducer 178. The divider 184 therefore produces anoutput voltage indicative of the current in the coil 30 divided by thedistance squared (I/d²).

[0664] The output voltage from the divider 184 is then applied to amultiplier 186. The multiplier 186 multiplies the output voltage fromthe divider 184 by a reference voltage Vref₅. The reference voltageVref₅ corresponds to a conversion factor for converting the value of(I/d²) to a value indicative of force in Newtons being applied by themovable central piece 16 against the cornea 4. The output voltage fromthe multiplier 186 is therefore indicative of the force in Newtons beingapplied by the movable central piece 16 against the cornea.

[0665] Next, the output voltage from the multiplier 186 is applied to aninput terminal of a divider 188. The other input terminal of the divider188 receives a reference voltage Vref₆. The reference voltage Vref₆corresponds to a calibration constant for converting force (in Newtons)to pressure (in Pascals) depending on the surface area of the movablecentral piece's substantially flat inner side 24. The output voltagefrom the divider 188 is therefore indicative of the pressure (inPascals) being exerted by the cornea 4 against the inner side of themovable central piece 16 in response to displacement of the movablecentral piece 16.

[0666] Since the pressure exerted by the cornea 4 depends upon thesurface area of the substantially flat inner side 24, the output voltagefrom the divider 188 is indicative of intraocular pressure only when thecornea 4 is being applanated by the entire surface area of the innerside 24. This, in turn, corresponds to the predetermined amount ofapplanation.

[0667] Preferably, the output voltage indicative of intraocular pressureis applied to an input terminal of a multiplier 190. The multiplier 190has another input terminal connected to a reference voltage Vref₇. Thereference voltage Vref₇ corresponds to a conversion factor forconverting pressure in Pascals to pressure in millimeters of mercury(mmHg). The voltage output from the multiplier 190 therefore isindicative of intraocular pressure in millimeters of mercury (mmHg)whenever the predetermined amount of applanation is achieved.

[0668] The output voltage from the multiplier 190 is then applied to thedisplay 167 which provides a visual display of intraocular pressurebased on this output voltage. Preferably, the display 167 or calculationunit 10 includes a memory device 33 which stores a pressure valueassociated with the output voltage from the multiplier 190 whenever thepredetermined amount of applanation is achieved. Since the currentproducing circuitry 32 is automatically and immediately deactivated uponachieving the predetermined amount of applanation, the intraocularpressure corresponds to the pressure value associated with the peakoutput voltage from the multiplier 190. The memory therefore can betriggered to store the highest pressure value upon detecting a drop inthe output voltage from the multiplier 190. Preferably, the memory isautomatically reset prior to any subsequent measurements of intraocularpressure.

[0669] Although FIG. 6 shows the display 167 in digital form, it isunderstood that the display 167 may have any known form. The display 167may also include the three LEDs 40A,40B,40C 163. illustrated in FIG. 1which give a visual indication of pressure ranges which, in turn, arecalibrated for each patient.

[0670] As indicated above, the illustrated calculation unit 10 includesseparate and distinct multipliers 180,182,186,190 and dividers 184,188for converting the output voltage indicative of current into an outputvoltage indicative of intraocular pressure in millimeters of mercury(mmHg). The separate and distinct multipliers and dividers arepreferably provided so that variations in the system's characteristicscan be compensated for by appropriately changing the reference voltagesVref₄, Vref₅, Vref₆ and/or Vref₇. It is understood, however, that whenall of the system's characteristics remain the same (e.g., the surfacearea of the inner side 24 and the desired distance separating thecontact device 2 from the actuation apparatus 6 and detectingarrangement 8) and the conversion factors do not change, that a singleconversion factor derived from the combination of each of the otherconversion factors can be used along with a single multiplier or dividerto achieve the results provided by the various multipliers and dividersshown in FIG. 6.

[0671] Although the above combination of elements is generally effectiveat accurately measuring intraocular pressure in a substantial majorityof patients, some patients have unusually thin or unusually thickcorneas. This, in turn, may cause slight deviations in the measuredintraocular pressure. In order to compensate for such deviations, thecircuitry of FIG. 6 may also include a variable gain amplifier 191(illustrated in FIG. 7A) connected to the output from the multiplier190. For the majority of patients, the variable gain amplifier 191 isadjusted to provide a gain (g) of one. The variable gain amplifier 191therefore would have essentially no effect on the output from themultiplier 190.

[0672] However, for patients with unusually thick corneas, the gain (g)is adjusted to a positive gain less than one. A gain (g) of less thanone is used because unusually thick corneas are more resistant toapplanation and consequently result in a pressure indication thatexceeds, albeit by a small amount, the actual intraocular pressure. Theadjustable gain amplifier 191 therefore reduces the output voltage fromthe multiplier 190 by a selected percentage proportional to the cornea'sdeviation from normal corneal thickness.

[0673] For patients with unusually thin corneas, the opposite effectwould be observed. Accordingly, for those patients, the gain (g) isadjusted to a positive gain greater than one so that the adjustable gainamplifier 191 increases the output voltage from the multiplier 190 by aselected percentage proportional to the cornea's deviation from normalcorneal thickness.

[0674] Preferably, the gain (g) is manually selected for each patientusing any known means for controlling the gain of a variable gainamplifier, for example, a potentiometer connected to a voltage source.As indicated above, the particular gain (g) used depends on thethickness of each patient's cornea which, in turn, can be determinedusing known corneal pachymetry techniques. Once the corneal thickness isdetermined, the deviation from the normal thickness is calculated andthe gain (g) is set accordingly.

[0675] Alternatively, as illustrated in FIG. 7B, the gain (g) may beselected automatically by connecting an output (indicative of cornealthickness) from a known pachymetry apparatus 193 to a buffer circuit195. The buffer circuit 195 converts the detected corneal thickness to again signal associated with the detected thickness' deviation from thenormal corneal thickness. In particular, the gain signal produces a gain(g) of one when the deviation is zero, produces a gain (g) greater thanone when the detected corneal thickness is less than the normalthickness, and produces a gain (g) less than one when the detectedcorneal thickness is greater than the normal thickness.

[0676] Although FIGS. 7A and 7B illustrate a configuration whichcompensates only for corneal thickness, it is understood that similarconfigurations can be used to compensate for corneal curvature, eyesize, ocular rigidity, and the like. For levels of corneal curvaturewhich are higher than normal, the gain would be less than one. The gainwould be greater than one for levels of corneal curvature which areflatter than normal. Typically, each increase in one diopter of cornealcurvature is associated with a 0.34 mm Hg increase in pressure. Theintraocular pressure rises 1 mm Hg for very 3 diopters. The gaintherefore can be applied in accordance with this general relationship.

[0677] In the case of eye size compensation, larger than normal eyeswould require a gain which is less than one, while smaller than normaleyes would require a gain which is greater than one.

[0678] For patients with “stiffer” than normal ocular rigidities, thegain is less than one, but for patients with softer ocular rigidities,the gain is greater than one.

[0679] As when compensating for corneal thickness, the gain may bemanually selected for each patient, or alternatively, the gain may beselected automatically by connecting the apparatus of the presentinvention to a known keratometer when compensating for cornealcurvature, and/or a known biometer when compensating for eye size.

[0680] Despite not being illustrated, it is understood that the systemincludes a power supply mechanism for selectively powering the systemusing either batteries or household AC current.

[0681] Operation of the preferred circuitry will now be described.Initially, the contact device 2 is mounted on the corneal surface of apatient and tends to locate itself centrally at the front of the cornea4 in essentially the same way as conventional contact lenses. Thepatient then looks through the central sight hole 38 at the intersectionof the cross-hairs which define the mark 70, preferably, while the light75 provided inside the tubular housing 64 is illuminated to facilitatevisualization of the cross-hairs and the reflected image 74. A roughalignment is thereby achieved.

[0682] Next, the preferred circuitry provides indications ofmisalignment or improper axial distance should either or both exist. Thepatient responds to such indications by taking the indicated correctiveaction.

[0683] Once proper alignment is achieved and the proper axial distanceexists between the actuation apparatus 6 and the contact device 2,push-action switch 164 is activated and the AND-gate 158 and start/stopswitch 156 activate the current producing circuitry 32. In response toactivation, the current producing circuitry 32 generates theprogressively increasing current in the coil 30. The progressivelyincreasing current creates a progressively increasing magnetic field inthe coil 30. The progressively increasing magnetic field, in turn,causes axial displacement of the movable central piece 16 toward thecornea 4 by virtue of the magnetic field's repulsive effect on themagnetically responsive element 26. Since axial displacement of themovable central piece 16 produces a progressively increasing applanationof the cornea 4, the reflected beams 60,62 begin to swing angularlytoward the light sensors 48,50. Such axial displacement and increasingapplanation continues until both reflected beams 60,62 reach the lightsensors 48,50 and the predetermined amount of applanation is therebydeemed to exist. At that instant, the current producing circuit 32 isdeactivated by the input 160 to AND-gate 158; the speaker 154 ismomentarily activated to give an audible indication that applanation hasbeen achieved; and the intraocular pressure is stored in the memorydevice 33 and is displayed on display 167.

[0684] Although the above-described and illustrated embodiment includesvarious preferred elements, it is understood that the present inventionmay be achieved using various other individual elements. For example,the detecting arrangement 8 may utilize various other elements,including elements which are typically utilized in the art of barcodereading.

[0685] With reference to FIGS. 8A and 8B, a contact device 2′ may beprovided with a barcode-like pattern 300 which varies in response todisplacement of the movable central piece 16′. FIG. 8A illustrates thepreferred pattern 300 prior to displacement of the movable central piece16′; and FIG. 8B shows the preferred pattern 300 when the predeterminedamount of applanation is achieved. The detecting arrangement thereforewould include a barcode reader directed generally toward the contactdevice 2′ and capable of detecting the differences in the barcodepattern 300.

[0686] Alternatively, as illustrated in FIGS. 9A and 9E, the contactdevice 2′ may be provided with a multi-color pattern 310 which varies inresponse to displacement of the movable central piece 16′. FIG. 9Aschematically illustrates the preferred color pattern 310 prior todisplacement of the movable central piece 16′, while FIG. 9Bschematically shows the preferred pattern 310 when the predeterminedamount of applanation is achieved. The detecting arrangement thereforewould include a beam emitter for emitting a beam of light toward thepattern 310 and a detector which receives a reflected beam from thepattern 310 and detects the reflected color to determine whetherapplanation has been achieved.

[0687] Yet another way to detect the displacement of the movable centralpiece 16 is by using a two dimensional array photosensor that senses thelocation of a reflected beam of light. Capacitive and electrostaticsensors, as well as changes in magnetic field can then be used to encodethe position of the reflected beam and thus the displacement of themovable central piece 16.

[0688] According to yet another alternative embodiment illustrated inFIG. 10, a miniature LED 320 is inserted into the contact device 2′. Thepiezoelectric ceramic is driven by ultrasonic waves or is alternativelypowered by electromagnetic waves. The brightness of the miniature LED320 is determined by the current flowing through the miniature LED 320which, in turn, maybe modulated by a variable resistance 330. The motionof the movable central piece 16′ varies the variable resistance 330.Accordingly, the intensity of light from the miniature LED 320 indicatesthe magnitude of the movable central piece's displacement. A miniature,low-voltage primary battery 340 may be inserted into the contact device2′ for powering the miniature LED 320.

[0689] With regard to yet another preferred embodiment of the presentinvention, it is understood that a tear film typically covers the eyeand that a surface tension resulting therefrom may cause underestimationof the intraocular pressure. Accordingly, the contact device of thepresent invention preferably has an inner surface of hydrophobicflexible material in order to decrease or eliminate this potentialsource of error.

[0690] It should be noted that the drawings are merely schematicrepresentations of the preferred embodiments. Therefore, the actualdimensions of the preferred embodiments and physical arrangement of thevarious elements is not limited to that which is illustrated. Variousarrangements and dimensions will become readily apparent to those ofordinary skill in the art. The size of the movable central piece, forexample, can be modified for use in animals or experimental techniques.Likewise, the contact device can be made with smaller dimensions for usewith infants and patients with eye lid abnormalities.

[0691] One preferred arrangement of the present invention includes ahandle portion extending out from below the housing 64 and connecteddistally to a platform. The platform acts as a base for placement on aplanar surface (e.g., a table), with the handle projecting up therefromto support the actuation apparatus 6 above the planar surface.

Indentation

[0692] The contact device 2 and associated system illustrated in FIGS.1-5 may also be used to detect intraocular pressure by indentation. Whenindentation techniques are used in measuring intraocular pressure, apredetermined force is applied against the cornea using an indentationdevice. Because of the force, the indentation device travels in towardthe cornea, indenting the cornea as it travels. The distance travelledby the indentation device into the cornea in response to thepredetermined force is known to be inversely proportional to intraocularpressure. Accordingly, there are various known tables which, for certainstandard sizes of indentation devices and standard forces, correlate thedistance travelled and intraocular pressure.

[0693] In utilizing the illustrated arrangement for indentation, themovable central piece 16 of the contact device 2 functions as theindentation device. In addition, the current producing circuit 32 isswitched to operate in an indentation mode. When switched to theindentation mode, the current producing circuit 32 supplies apredetermined amount of current through the coil 30. The predeterminedamount of current corresponds to the amount of current needed to produceone of the aforementioned standard forces.

[0694] The predetermined amount of current creates a magnetic field inthe actuation apparatus 6. This magnetic field, in turn, causes themovable central piece 16 to push inwardly against the cornea 4 via theflexible membrane 14. Once the predetermined amount of current has beenapplied and a standard force presses against the cornea, it is necessaryto determine how far the movable central piece 16 moved into the cornea4.

[0695] Accordingly, when measurement of intraocular pressure byindentation is desired, the system illustrated in FIG. 1 furtherincludes a distance detection arrangement for detecting a distancetravelled by the movable central piece 16, and a computation portion 199in the calculation unit 10 for determining intraocular pressure based onthe distance travelled by the movable central piece 16 in applying thepredetermined amount of force.

[0696] A preferred indentation distance detection arrangement 200 isillustrated in FIGS. 11A and 11B and preferably includes a beam emitter202 and a beam sensor 204. Preferably, lenses 205 are disposed in theoptical path between the beam emitter 202 and beam sensor 204. The beamemitter 202 is arranged so as to emit a beam 206 of light toward themovable central piece 16. The beam 206 of light is reflected back fromthe movable central piece 16 to create a reflected beam 208. The beamsensor 204 is positioned so as to receive the reflected beam 208whenever the device 2 is located at the proper axial distance and inproper alignment with the actuation apparatus 6. Preferably, the properdistance and alignment are achieved using all or any combination of theaforementioned sighting mechanism, optical alignment mechanism andoptical distance measuring mechanism.

[0697] Once proper alignment and the proper axial distance are achieved,the beam 206 strikes a first portion of the movable central piece 16, asillustrated in FIG. 11A. Upon reflection of the beam 206, the reflectedbeam 208 strikes a first portion of the beam sensor 204. In FIG. 11A,the first portion is located on the beam sensor 204 toward the rightside of the drawing.

[0698] However, as indentation progresses, the movable central piece 16becomes more distant from the beam emitter 202. This increase indistance is illustrated in FIG. 11A. Since the movable central piece 16moves linearly away, the beam 206 strikes progressively more to the lefton the movable central piece 16. The reflected beam 206 therefore shiftstoward the left and strikes 204 at a second portion which is to the leftof the first portion.

[0699] The beam sensor 204 is arranged so as to detect the shift in thereflected beam 206, which shift is proportional to the displacement ofthe movable central piece 16. Preferably, the beam sensor 204 includesan intensity responsive beam detector 212 which produces an outputvoltage proportional to the detected intensity of the reflected beam 208and an optical filter element 210 which progressively filters more lightas the light's point of incidence moves from one portion of the filterto an opposite portion.

[0700] In FIGS. 11A and 11B, the optical filter element 210 comprises afilter with a progressively increasing thickness so that light passingthrough a thicker portion has a more significantly reduced intensitythan light passing through a thinner portion of the filter.Alternatively, the filter can have a constant thickness andprogressively increasing filtering density whereby a progressivelyincreasing filtering effect is achieved as the point of incidence movesacross a longitudinal length of the filter.

[0701] When, as illustrated in FIG. 11A, the reflected beam 208 passesthrough a thinnest portion of the optical filter element 210 (e.g.,prior to indentation), the reflected beam's intensity is reduced by onlya small amount. The intensity responsive beam detector 212 thereforeprovides a relatively high output voltage indicating that no movement ofthe movable central piece 16 toward the cornea 4 has occurred.

[0702] However, as indentation progresses, the reflected beam 208progressively shifts toward thicker portions of the optical filterelement 210 which filter more light. The intensity of the reflected beam208 therefore decreases proportionally to the displacement of themovable central piece 16 toward the cornea 4. Since the intensityresponsive beam detector 212 produces an output voltage proportional tothe reflected beam's intensity, this output voltage decreasesprogressively as the displacement of the movable central piece 16increases. The output voltage from the intensity responsive beamdetector 212 is therefore indicative of the movable central piece'sdisplacement.

[0703] Preferably, the computation portion 199 is responsive to thecurrent producing circuitry 32 so that, once the predetermined amount offorce is applied, the output voltage from the beam detectors 212 isreceived by the computation portion 199. The computation portion then,based on the displacement associated with the particular output voltage,determines intraocular pressure. Preferably, the memory 33 includes amemory location for storing a value indicative of the intraocularpressure.

[0704] Also, the computation portion 199 preferably has access to anelectronically or magnetically stored one of the aforementioned knowntables. Since the tables indicate which intraocular pressure correspondswith certain distances traveled by the movable central piece 16, thecomputation portion 199 is able to determine intraocular pressure bymerely determining which pressure corresponds with the distance traveledby the movable central piece 16.

[0705] The system of the present invention may also be used to calculatethe rigidity of the sclera. In particular, the system is first used todetermine intraocular pressure by applanation and then is used todetermine intraocular pressure by indentation. The differences betweenthe intraocular pressures detected by the two methods would then beindicative of the sclera's rigidity.

[0706] Although the foregoing description of the preferred systemsgenerally refers to a combined system capable of detecting intraocularpressure by both applanation and indentation, it is understood that acombined system need not be created. That is, the system capable ofdetermining intraocular pressure by applanation may be constructedindependently from a separate system for determining intraocularpressure by indentation and vice versa.

Measuring Hydrodynamics of the Eye

[0707] The indentation device of the present invention may also beutilized to non-invasively measure hydrodynamics of an eye includingoutflow facility. The method of the present invention: preferablycomprises several steps including the following:

[0708] According to a first step, an indentation device is placed incontact with the cornea. Preferably, the indentation device comprisesthe contact device 2 illustrated in FIGS. 1 and 2A-2D.

[0709] Next, at least one movable portion of the indentation device ismoved in toward the cornea using a first predetermined amount of forceto achieve indentation of the cornea. When the indentation device is thecontact device 2, the movable portion consists of the movable centralpiece 16.

[0710] An intraocular pressure is then determined based on a firstdistance traveled toward the cornea by the movable portion of theindentation device during application of the first predetermined amountof force. Preferably, the intraocular pressure is determined using theaforementioned system for determining intraocular pressure byindentation.

[0711] Next, the movable portion of the indentation device is rapidlyreciprocated in toward the cornea and away from the cornea at a firstpredetermined frequency and using a second predetermined amount of forceduring movement toward the cornea to thereby force intraocular fluid outfrom the eye. The second predetermined amount of force is preferablyequal to or greater than the first predetermined amount of force. It isunderstood, however, that the second predetermined amount of force maybe less than the first predetermined amount of force. The reciprocation,which preferably continues for 5 seconds, should generally not exceed 10seconds induration.

[0712] The movable portion is then moved in toward the cornea using athird predetermined amount of force to again achieve indentation of thecornea.

[0713] A second intraocular pressure is then determined based on asecond distance traveled toward the cornea by the movable portion of theindentation device during application of the third predetermined amountof force. This second intraocular pressure is also preferably determinedusing the aforementioned system for determining intraocular pressure byindentation. Since intraocular pressure decreases as a result of forcingintraocular fluid out of the eye during the rapid reciprocation of themovable portion, it is generally understood that, unless the eye is sodefective that no fluid flows out therefrom, the second intraocularpressure will be less than the first intraocular pressure. Thisreduction in intraocular pressure is indicative of outflow facility.

[0714] Next, the movable portion of the indentation device is againrapidly reciprocated in toward the cornea and away from the cornea, butat a second predetermined frequency and using a fourth predeterminedamount of force during movement toward the cornea. The fourthpredetermined amount of force is preferably equal or greater than thesecond predetermined amount of force. It is understood, however, thatthe fourth predetermined amount of force may be less than the secondpredetermined amount of force. Additional intraocular fluid is therebyforced out from the eye. This reciprocation, which also preferablycontinues for 5 seconds, should generally not exceed 10 seconds induration.

[0715] The movable portion is subsequently moved in toward the corneausing a fifth predetermined amount of force to again achieve indentationof the cornea.

[0716] Thereafter, a third intraocular pressure is determined based on athird distance traveled toward the cornea by the movable portion of theindentation device during application of the fifth predetermined amountof force.

[0717] The differences are then preferably calculated between the first,second, and third distances, which differences are indicative of thevolume of intraocular fluid which left the eye and therefore are alsoindicative of the outflow facility. It is understood that the differencebetween the first and last distances may be used, and in this regard, itis not necessary to use the differences between all three distances. Infact, the difference between any two of the distances will suffice.

[0718] Although the relationship between the outflow facility and thedetected differences varies when the various parameters of the methodand the dimensions of the indentation device change, the relationshipfor given parameters and dimensions can be easily determined by knownexperimental techniques and/or using known Friedenwald Tables.

[0719] The method of the present invention is preferably carried outusing an indenting surface which is three millimeters in diameter and acomputer equipped with a data acquisition board. In particular, thecomputer generates the predetermined forces via a digital-to-analog(D/A) converter connected to the current generating circuitry 32. Thecomputer then receives signals indicative of the first, second, andthird predetermined distances via an analog-to-digital (A/D) converter.These signals are analyzed by the computer using the aforementionedrelationship between the differences in distance and the outflowfacility. Based on this analysis, the computer creates an output signalindicative of outflow facility. The output signal is preferably appliedto a display screen which, in turn, provides a visual indication ofoutflow facility.

[0720] Preferably, the method further comprises the steps of plottingthe differences between the first, second, and third distances to acreate a graph of the differences and comparing the resulting graph ofdifferences to that of a normal eye to determine if any irregularitiesin outflow facility are present. As indicated above, however, it isunderstood that the difference between the first and last distancesmaybe used, and in this regard, it is not necessary to use thedifferences between all three distances. In fact, the difference betweenany two of the distances will suffice.

[0721] Preferably, the first predetermined frequency and secondpredetermined frequency are substantially equal and are approximately 20Hertz. Generally, any frequencies up to 35 Hertz can be used, thoughfrequencies below 1 Hertz are generally less desirable because thestress relaxation of the eye's outer coats would contribute to changesin pressure and volume.

[0722] The fourth predetermined amount of force is preferably at leasttwice the second predetermined amount of force, and the thirdpredetermined amount of force is preferably approximately half of thefirst predetermined amount of force. It is understood, however, thatother relationships will suffice and that the present method is notlimited to the foregoing preferred relationships.

[0723] According to a preferred use of the method, the firstpredetermined amount of force is between 0.01 Newton and 0.015 Newton;the second predetermined amount of force is between 0.005 Newton and0.0075 Newton; the third predetermined amount of force is between 0.005Newton and 0.0075 Newton; the fourth predetermined amount of force isbetween 0.0075 Newton and 0.0125 Newton; the fifth predetermined amountof force is between 0.0125 Newton and 0.025 Newton; the firstpredetermined frequency is between 1 Hertz and 35 Hertz; and the secondpredetermined frequency is also between 1 Hertz and 35 Hertz. Thepresent method, however, is not limited to the foregoing preferredranges.

[0724] Although the method of the present invention is preferablycarried out using the aforementioned device, it is understood thatvarious other tonometers may be used. The method of the presentinvention therefore is not limited in scope to its use in conjunctionwith the claimed system and illustrated contact device.

Alternative Embodiments of the Contact Device

[0725] Although the foregoing description utilizes an embodiment of thecontact device 2 which includes a flexible membrane 14 on the insidesurface of the contact device 2, it is readily understood that thepresent invention is not limited to such an arrangement. Indeed, thereare many variations of the contact device which fall well within thescope of the present invention.

[0726] The contact device 2, for example, may be manufactured with noflexible membrane, with the flexible membrane on the outside surface ofthe contact device 2 (i.e., the side away from the cornea), with theflexible membrane on the inside surface of the contact device 2, or withthe flexible membrane on both sides of the contact device 2.

[0727] Also, the flexible membrane (s) 14 can be made to have an annularshape, thus permitting light to pass undistorted directly to the movablecentral piece 16 and the cornea for reflection thereby.

[0728] In addition, as illustrated in FIG. 12, the movable central piece16 may be formed with a similar annular shape so that a transparentcentral portion thereof merely contains air. This way, light passingthrough the entire contact device 2 impinges directly on the corneawithout undergoing any distortion due to the contact device 2.

[0729] Alternatively, the transparent central portion can be filled witha transparent solid material. Examples of such transparent solidmaterials include polymethyl methacrylate, glass, hard acrylic, plasticpolymers, and the like. According to a preferred arrangement, glasshaving an index of refraction substantially greater than that of thecornea is utilized to enhance reflection of light by the cornea when thelight passes through the contact device 2. Preferably, the index ofrefraction for the glass is greater than 1.7, compared to the typicalindex of refraction of 1.37 associated with the cornea.

[0730] It is understood that the outer surface of the movable centralpiece 16 may be coated with an anti-reflection layer in order toeliminate extraneous reflections from that surface which might otherwiseinterfere with operation of the alignment mechanism and the applanationdetecting arrangement.

[0731] The interconnections of the various components of the contactdevice 2 are also subject to modification without departing from thescope and spirit of the present invention. It is understood thereforethat many ways exist for interconnecting or otherwise maintaining theworking relationship between the movable central piece 16, the rigidannular member 12, and the membranes 14.

[0732] When one or two flexible membranes 14 are used, for example, thesubstantially rigid annular member 12 can be attached to any one or bothof the flexible membrane(s) 14 using any known attachment techniques,such as gluing, heat-bonding, and the like. Alternatively, when twoflexible membranes 14 are used, the components may be interconnected orotherwise maintained in a working relationship, without having todirectly attach the flexible membrane 14 to the substantially rigidannular member 12. Instead, the substantially rigid annular member 12may be retained between the two flexible membranes 14 by bonding themembranes to one another about their peripheries while the rigid annularmember 12 is sandwiched between the membranes 14.

[0733] Although the movable central piece 16 may be attached to theflexible membrane(s) 14 by gluing, heat-bonding, and the like, it isunderstood that such attachment is not necessary. Instead, one or bothof the flexible membranes 14 can be arranged so as to completely orpartially block the movable central piece 16 and prevent it from fallingout of the hole in the substantially rigid annular member 12. When theaforementioned annular version of the flexible membranes 14 is used, asillustrated by way of example in FIG. 12, the diameter of the hole in atleast one of the annular flexible membranes 14 is preferably smallerthan that of the hole in the substantially rigid annular member 12 sothat a radially inner portion 14A of the annular flexible membrane 14overlaps with the movable central piece 16 and thereby prevents themovable central piece 16 from falling out of the hole in thesubstantially rigid annular member 12.

[0734] As illustrated in FIG. 13A, another way of keeping the movablecentral piece 16 from falling out of the hole in the substantially rigidannular member 12 is to provide arms 16A which extend radially out fromthe movable central piece 16 and are slidably received in respectivegrooves 16B. The grooves 16B are formed in the rigid annular member 12.Each groove 16B has a longitudinal dimension (vertical in FIG. 13) whichis selectively chosen to restrict the range of movement of the movablecentral piece 16 to within predetermined limits. Although FIG. 13 showsan embodiment wherein the grooves are in the substantially rigid annularmember 12 and the arms extend out from the movable central piece 16, itis understood that an equally effective arrangement can be created byreversing the configuration such that the grooves are located in themovable central piece 16 and the arms extend radially in from thesubstantially rigid annular member 12.

[0735] Preferably, the grooves 16B include resilient elements, such asminiature springs, which bias the position of the movable central piece16 toward a desired starting position. In addition, the arms 16A mayinclude distally located miniature wheels which significantly reduce thefriction between the arms 16A and the walls of the grooves 16B.

[0736]FIG. 13B illustrates another way of keeping the movable centralpiece 16 from falling out of the hole in the substantially rigid annularmember 12. In FIG. 13B, the substantially rigid annular member 12 isprovided with radially inwardly extending flaps 12F at the outer surfaceof the annular member 12. One of the aforementioned annular membranes 14is preferably disposed on the inner side of the substantially rigidannular member 12. Preferably, a portion of the membrane 14 extendsradially inwardly past the walls of the rigid annular member's hole. Thecombination of the annular membrane 14 and the flaps 12F keeps themovable central piece 16 from falling out of the hole in thesubstantially rigid annular member 12.

[0737] The flaps 12F may also be used to achieve or facilitate actuationof the movable central piece 16. In a magnetically actuated embodiment,for example, the flaps 12F may be magnetized so that the flaps 12F moveinwardly in response to an externally applied magnetic field.

[0738] With reference to FIG. 14, an alternative embodiment of thecontact device 2 is made using a soft contact lens material 12A having aprogressively decreasing thickness toward its outer circumference. Acylindrical hole 12B is formed in the soft contact lens material 12A.The hole 12B, however, does not extend entirely through the soft contactlens material 12A. Instead, the hole has a closed bottom defined by athin portion 12C of the soft contact lens material 12A. The movablecentral piece 16 is disposed slidably within the hole 12B, andpreferably, the thin portion 12C is no more than 0.2 millimeters thick,thereby allowing the movable central piece 16 to achieve applanation orindentation when moved against the closed bottom of the hole toward thecornea with very little interference from the thin portion 12C.

[0739] Preferably, a substantially rigid annular member 12D is insertedand secured to the soft contact material 12A to define a more stablewall structure circumferentially around the hole 12B. This, in turn,provides more stability when the movable central piece 16 moves in thehole 12B.

[0740] Although the soft lens material 12A preferably comprisesHydrogel, silicone, flexible acrylic, or the like, it is understood thatany other suitable materials may be used. In addition, as indicatedabove, any combination of flexible membranes may be added to theembodiment of FIG. 14. Although the movable central piece 16 in FIG. 14is illustrated as being annular, it is understood that any other shapemay be utilized. For example, any of the previously described movablecentral pieces 16 would suffice.

[0741] Similarly, the annular version of the movable central piece 16may be modified by adding a transparent bottom plate (not illustrated)which defines a flat transparent bottom surface of the movable centralpiece 16. When modified in this manner, the movable central piece 16would have a generally cup-shaped appearance. Preferably, the flattransparent bottom surface is positioned toward the cornea to enhancethe flattening effect of the movable central piece 16; however, it isunderstood that the transparent plate can be located on the outsidesurface of the movable central piece 16 if desired.

[0742] Although the movable central piece 16 and the hole in thesubstantially rigid annular member 12 (or the hole in the soft contactlens material 12A) are illustrated as having complementary cylindricalshapes, it is understood that the complementary shapes are not limitedto a cylinder, but rather can include any shape which permits sliding ofthe movable central piece 16 with respect to its surrounding structure.

[0743] It is also understood that the movable central piece 16 may bemounted directly onto the surface of a flexible membrane 14 withoutusing a substantially rigid annular member 12. Although such anarrangement defines a working embodiment of the contact device 2, itsstability, accuracy, and level of comfort are significantly reducedcompared to that of a similar embodiment utilizing the substantiallyrigid annular member 12 with a progressively tapering periphery.

[0744] Although the illustrated embodiments of the movable central piece16 include generally flat outside surfaces with well defined lateraledges, it is understood that the present invention is not limited tosuch arrangements. The present invention, for example, can include amovable central piece 16 with a rounded outer surface to enhance comfortand/or to coincide with the curvature of the outer surface of thesubstantially rigid annular member 12. The movable central piece canalso be made to have any combination of curved and flat surfaces definedat its inner and outer surfaces, the inner surface being the surface atthe cornea and the outer surface being the surface directed generallyaway from the cornea.

[0745] With reference to FIG. 15, the movable central piece 16 may alsoinclude a centrally disposed projection 16P directed toward the cornea.The projection 16P is preferably created by extending the transparentsolid material in toward the cornea at the center of the movable centralpiece 16.

Alternative Embodiment for Measuring Intraocular Pressure by Applanation

[0746] With reference to FIG. 16, an alternative embodiment of thesystem for measuring intraocular pressure by applanation will now bedescribed. The alternative embodiment preferably utilizes the version ofthe contact device 2 which includes a transparent central portion.

[0747] According to the alternative embodiment, the schematicallyillustrated coil 30 of the actuation apparatus includes an iron core 30Afor enhancing the magnetic field produced by the coil 30. The iron core30A preferably has an axially extending bore hole 30B (approximately 6millimeters in diameter) which permits the passage of light through theiron core 30A and also permits mounting of two lenses L3 and L4 therein.

[0748] In order for the system to operate successfully, the strength ofthe magnetic force applied by the coil 30 on the movable central piece16 should be sufficient to applanate patients' corneas over at least thefull range of intraocular pressures encountered clinically (i.e. 5-50 mmHg). According to the illustrated alternative embodiment, intraocularpressures ranging from 1 to over 100 mm of mercury can be evaluatedusing the present invention. The forces necessary to applanate againstsuch intraocular pressures may be obtained with reasonablystraightforward designs and inexpensive materials as will bedemonstrated by the following calculations:

[0749] It is known that the force F exerted by an external magneticfield on a small magnet equals the magnet's magnetic dipole moment mmultiplied by the gradient of the external field's magnetic inductionvector “grad B” acting in the direction of the magnet's dipole moment.

F=m*gradB  (1)

[0750] The magnetic dipole moment m for the magnetic version of themovable central piece 16 can be determined using the following formula:

m=(B*V)/u ₀  (2)

[0751] where B is the magnetic induction vector just at the surface ofone of the poles of the movable central piece 16, V is its volume, andu₀ is the magnetic permeability of free space which has a value of12.57*10⁻⁷ Henry/meter.

[0752] A typical value of B for magnetized Alnico movable central pieces16 is 0.5 Tesla. If the movable central piece 16 has a thickness of 1mm, a diameter of 5 mm, and 50% of its initial volume is machined away,its volume V 9.8 cubic millimeters (9.8*10⁻⁹ cubic meters. Substitutingthese values into Equation 2 yields the value for the movable centralpiece's magnetic dipole moment, namely, m=0.00390 Amp*(Meter)².

[0753] Using the foregoing calculations, the specifications of theactuation apparatus can be determined. The magnetic field gradient “gradB” is a function of the distance x measured from the front face of theactuation apparatus and may be calculated as follows: $\begin{matrix}{{{grad}\quad B} = \frac{u_{0}*X*N*{I({RAD})}^{2}*\left\{ {\left\lbrack {\left( {x + L} \right)^{2} + {RAD}^{2}} \right\rbrack^{{- 3}/2} - \left\lbrack {x^{2} + {RAD}^{2}} \right\rbrack^{{- 3}/2}} \right\}}{2*L}} & (3)\end{matrix}$

[0754] where X is the magnetic susceptibility of the iron core, N is thenumber of turns in the coil's wire, I is the electric current carried bythe wire, L is the length of the coil 30, and RAD is the radius of thecoil 30.

[0755] The preferred values for these parameters in the alternativeembodiment are: X=500, N=200, I=1.0 Amp, L=0.05 meters, and RAD=0.025meters. It is understood, however, that the present invention is notlimited to these preferred parameters. As usual, u₀=12.57*10⁻⁷Henry/meter.

[0756] The force F exerted by the magnetic actuation apparatus on themovable central piece 16 is found from Equation 1 using theaforementioned preferred values as parameters in Equation 3, and theabove result for m=0.00390 Amp*(Meter)². A plot of F as a function ofthe distance x separating the movable central piece 16 from the pole ofthe magnetic actuation apparatus appears as FIG. 16A.

[0757] Since a patient's cornea 4, when covered by the contact device 2which holds the movable central piece 16, can be placed conveniently ata distance x=2.5 cm (0.025 m) from the actuation apparatus, it is notedfrom FIG. 16A that the magnetic actuation force is approximately F=0;063Newtons.

[0758] This force is then compared to F_(required) which is the forceactually needed to applanate a cornea 4 over a typical applanation areawhen the intraocular pressure is as high as 50 mm Hg. In Goldmantonometry, the diameter of the applanated area is approximately 3.1 mmand therefore the typical applanated AREA will equal 7.55 mm². Thetypical maximum pressure of 50 mm Hg can be converted to metric form,yielding a pressure of 0.00666 Newtons/mm². The value of F_(required)then can be determined using the following equation:

F _(required)=PRESSURE*AREA  (4)

[0759] After mathematical substitution, F_(required)=0.050 Newtons.Comparing the calculated magnetic actuation force F to the forcerequired F_(required), it becomes clear that F_(required) is less thanthe available magnetic driving force F. Therefore, the maximum forceneeded to applanate the cornea 4 for intraocular pressure determinationsis easily achieved using the actuation apparatus and movable centralpiece 16 of the present invention.

[0760] It is understood that, if a greater force becomes necessary forwhatever reason (e.g, to provide more distance between the contactdevice 2 and the actuation apparatus), the various parameters can bemanipulated and/or the current in the coil 30 can be increased toachieve a satisfactory arrangement.

[0761] In order for the actuation apparatus to properly actuate themovable central piece 16 in a practical way, the magnetic actuationforce (and the associated magnetic field) should increase from zero,reach a maximum in about 0.01 sec., and then return back to zero inapproximately another 0.01 sec. The power supply to the actuationapparatus therefore preferably includes circuitry and a power sourcecapable of driving a “current pulse” of peak magnitude in the 1 ampererange through a fairly large inductor (i.e. the coil 30).

[0762] For A single-pulse@ operation, a DC-voltage power supply can beused to charge a capacitor C through a charging resistor. One side ofthe capacitor is grounded while the other side (“high” side) may be at a50 volt DC potential. The “high” side of the capacitor can be connectedvia a high current-carrying switch to a “discharge circuit” consistingof the coil 30 and a damping resistor R. This arrangement yields anR-L-C series circuit similar to that which is conventionally used togenerate large pulses of electrical current for such applications asobtaining large pulsed magnetic fields and operating pulsed laser powersystems. By appropriately choosing the values of the electricalcomponents and the initial voltage of the capacitor, a A current pulse@of the kind described above can be generated and supplied to the coil 30to thereby operate the actuation apparatus.

[0763] It is understood, however, that the mere application of a currentpulse of the kind described above to a large inductor, such as the coil30, will not necessarily yield a zero magnetic field after the currentpulse has ended. Instead, there is usually an undesirable residualmagnetic field from the iron-core 30A even though no current is flowingin the coil 30. This residual field is caused by magnetic hysteresis andwould tend to produce a magnetic force on the movable central piece 16when such a force is not wanted.

[0764] Therefore, the alternative embodiment preferably includes meansfor zeroing the magnetic field outside the actuation apparatus afteroperation thereof. Such zeroing can be provided by a demagnetizingcircuit connected to the iron-core 30A.

[0765] Methods for demagnetizing an iron-core are generally known andare easy to implement. It can be done, for example, by reversing thecurrent in the coil repeatedly while decreasing its magnitude. Theeasiest way to do this is by using a step-down transformer where theinput is a sinusoidal voltage at 60 Hz which starts at a “line voltage”of 110 VAC and is gradually dampened to zero volts, and where the outputof the transformer is connected to the coil 30.

[0766] The actuation apparatus therefore may include two power circuits,namely, a “single pulse” current source used for conducting applanationmeasurements and a “demagnetization circuit” for zeroing the magneticfield of the coil 30 immediately after each applanation measurement.

[0767] As illustrated in FIG. 16 and more specifically in FIG. 17, thealternative embodiment used for applanation also includes an alternativeoptical alignment system. Alignment is very important because, asindicated by the graph of FIG. 16A, the force exerted by the actuationapparatus on the movable central piece 16 depends very much on theirrelative positions. In addition to the movable central piece's axiallocation with respect to the actuation apparatus (x-direction), themagnetic force exerted on the movable central piece 16 also depends onits lateral (y-direction) and vertical (z-direction) positions, as wellas on its orientation (tip and tilt) with respect to the central axis ofthe actuation apparatus.

[0768] Considering the variation of force F with axial distance x shownin FIG. 16A, it is clear that the movable central piece 16 should bepositioned in the x-direction with an accuracy of about +/−1 mm forreliable measurements. Similarly, since the diameter of the coil 30 ispreferably 50 mm, the location of the movable central piece 16 withrespect to the y and z directions (i.e. perpendicular to thelongitudinal axis of the coil 30) should be maintained to within +/−2 mm(a region where the magnetic field is fairly constant) of the coil'slongitudinal axis.

[0769] Finally, since the force on the movable central piece 16 dependson the cosine of the angle between the coil's longitudinal axis and thetip or tilt angle of the movable central piece 16, it is important thatthe range of the patient's gaze with respect to the coil's longitudinalaxis be maintained within about +/−2 degrees for reliable measurements.

[0770] In order to satisfy the foregoing criteria, the alternativeoptical alignment system facilitates precise alignment of the patient'scorneal vertex (situated centrally behind the movable central piece 16)with the coil's longitudinal axis, which precise alignment can beachieved independently by a patient without the assistance of a trainedmedical technician or health care professional.

[0771] The alternative optical alignment system functions according tohow light reflects and refracts at the corneal surface. For the sake ofsimplicity, the following description of the alternative opticalalignment system and FIGS. 16 and 17 does not refer specifically to theeffects of the movable central piece's transparent central portion onthe operation of the optical system, primarily because the transparentcentral portion of the movable central piece 16 is preferably arrangedso as not to affect the behavior of optical rays passing through themovable central piece 16.

[0772] Also, for the sake of simplicity, FIG. 17 does not show the ironcore 30A and its associated bore 30B, though it is understood that thealignment beam (described hereinafter) passes through the bored hole 30Band that the lenses L3 and L4 are mounted within the bored hole 30B.

[0773] As illustrated in FIG. 16, a point-like source 350 of light suchas an LED is located at the focal plane of a positive (i.e., convergent)lens L1. The positive lens L1 is arranged so as to collimate a beam oflight from the source 350. The collimated beam passes through a beamsplitter BS1 and a transmitted beam of the collimated beam continuesthrough the beam splitter BS1 to a positive lens L2. The positive lensL2 focuses the transmitted beam to a point within lens L3 located at thefocal plane of a lens L4. The light rays passing through L4 arecollimated once again and enter the patient's eye where they are focusedon the retina 5. The transmitted beam is therefore perceived by thepatient as a point-like light.

[0774] Some of the rays which reach the eye are reflected from thecorneal surface in a divergent manner due to the cornea's preapplanationcurvature, as shown in FIG. 18, and are returned back to the patient'seye by a partially mirrored planar surface of the lens L4. These raysare perceived by the patient as an image of the corneal reflection whichguides the patient during alignment of his/her eye in the instrument aswill be described hereinafter.

[0775] Those rays which are reflected by the convex cornea 4 and passfrom right-to-left through the lens L4 are made somewhat more convergentby the lens L4. From the perspective of lens L3, these rays appear tocome from a virtual point object located at the focal point. Therefore,after passing through L3, the rays are once again collimated and enterthe lens L2 which focuses the rays to a point on the surface of the beamsplitter BS1. The beam splitter BS1 is tilted at 45 degrees andconsequently deflects the rays toward a lens L5 which, in turn,collimates the rays. These rays then strike the surface of a tiltedreflecting beam splitter BS2. The collimated rays reflected from thebeam splitter BS2 enter lens L6 which focuses them onto the smallaperture of a silicon photodiode which functions as an alignment sensorD1.

[0776] Therefore, when the curved cornea 4 is properly aligned, anelectric current is produced by the alignment sensor D1. The alignmentsystem is very sensitive because it is a confocal arrangement (i.e., thepoint image of the alignment light due to the cornealreflection—Purkinje image—in its fiducial position is conjugate to thesmall light-sensitive aperture of the silicon photodiode). In thismanner, an electrical current is obtained from the alignment sensor onlywhen the cornea 4 is properly aligned with respect to the lens L4 which,in turn, is preferably mounted at the end of the magnetic actuationapparatus. The focal lengths of all the lenses shown in FIG. 17 arepreferably 50 mm except for the lens L3 which preferably has a focallength of 100 MM.

[0777] An electrical circuit capable of operating the alignment sensorD1 is straight-forward to design and build. The silicon photodiodeoperates without any bias voltage (“photovoltaic mode@) thus minimizinginherent detector noise. In this mode, a voltage signal, whichcorresponds to the light level on the silicon surface, appears across asmall resistor spanning the diode's terminals. Ordinarily this voltagesignal is too small for display or subsequent processing; however, itcan be amplified many orders of magnitude using a simple transimpedanceamplifier circuit. Preferably, the alignment sensor D1 is utilized inconjunction with such an amplified photodiode circuit.

[0778] Preferably, the circuitry connected to the alignment sensor D1 isarranged so as to automatically activate the actuation apparatusimmediately upon detecting via the sensor D1 the existence of properalignment. If, however, the output from the alignment sensor D1indicates that the eye is not properly aligned, the circuitry preferablyprevents activation of the actuation apparatus. In this way, thealignment sensor D1, not the patient, determines when the actuationapparatus will be operated.

[0779] As indicated above, the optical alignment system preferablyincludes an arrangement for guiding the patient during alignment ofhis/her eye in the instrument. Such arrangements are illustrated, by wayof example, in FIGS. 18 and 19.

[0780] The arrangement illustrated in FIG. 18 allows a patient toprecisely position his/her eye translationally in all x-y-z directions.In particular, the lens L4 is made to include a plano surface, the planosurface being made partially reflective so that a patient is able to seea magnified image of his/her pupil with a bright point source of lightlocated somewhere near the center of the iris. This point source imageis due to the reflection of the incoming alignment beam from the curvedcorneal surface (called the first Purkinje image) and its subsequentreflection from the mirrored or partially reflecting plano surface ofthe lens L4. Preferably, the lens L4 makes the reflected rays parallelas they return to the eye which focuses them onto the retina 5.

[0781] Although FIG. 18 shows the eye well aligned so that the rays arefocused at a central location on the surface of the retina 5, it isunderstood that movements of the eye toward or away (x—direction) fromthe lens L4 will blur the image of the corneal reflection, and thatmovements of the eye in either the y or z direction will tend todisplace the corneal reflection image either to the right/left orup/down.

[0782] The patient therefore performs an alignment operation by gazingdirectly at the alignment light and moving his/her eye slowly in threedimensions until the point image of the corneal reflection is as sharpas possible (x-positioning) and merges with the point image of thealignment light (y & z positioning) which passes straight through thecornea 4.

[0783] As illustrated in FIG. 19, the lens L4 need not have a partiallyreflective portion if the act of merely establishing a proper directionof gaze provides sufficient alignment.

[0784] Once alignment is achieved, a logic signal from the opticalalignment system activates the “pulse circuit” which, in turn, powersthe actuation apparatus. After the actuation apparatus is activated, themagnetic field at the patient's cornea increases steadily for a timeperiod of about 0.01 sec. The effect of this increasing field is toapply a steadily increasing force to the movable central piece 16resting on the cornea which, in turn, causes the cornea 4 to flattenincreasingly over time. Since the size of the applanation area isproportional to the force on the movable central piece 16 (andPressure=Force/Area), the intraocular pressure (IOP) is found bydetermining the ratio of the force to the area applanated by the force.

[0785] In order to detect the applanated area and provide an electricalsignal indicative of the size of the applanated area, the alternativeembodiment includes an applanation sensor D2. The rays that arereflected from the applanated corneal surface are reflected in agenerally parallel manner by virtue of the flat surface presented by theapplanated cornea 4. As the rays pass from right-to-left through thelens L4, they are focused within the lens L3 which, in turn, is in thefocal plane of the lens L2. Consequently, after passing through the lensL2, the rays are once again collimated and impinge on the surface ofbeam splitter BS1. Since the beam splitter BS1 is tilted at 45 degrees,the beam splitter BS1 deflects these collimated rays toward the lens L5which focuses the rays to a point at the center of beam splitter BS2.The beam splitter BS2 has a small transparent portion or hole in itscenter which allows the direct passage of the rays on to the lens L7(focal length of preferably 50 mm). The lens L7 pertains to anapplanation sensing arm of the alternative embodiment.

[0786] The focal spot on the beam splitter BS2 is in the focal plane ofthe lens L7. Consequently, the rays emerging from the lens L7 are onceagain collimated. These collimated rays impinge on the mirror Ml,preferably at a 45 degree angle, and are deflected toward a positivelens L8 (focal length of 50 mm) which focuses the rays onto the smallaperture of a silicon photodiode which defines the applanation sensorD2.

[0787] It is understood that rays which impinge upon the cornea 4slightly off center tend to be reflected away from the lens L4 when thecornea's curvature remains undisturbed. However, as applanationprogresses and the cornea becomes increasingly flat, more of these raysare reflected back into the lens L4. The intensity of light on theapplanation sensor D2 therefore increases, and as a result, an electriccurrent is generated by the applanation sensor D2, which electriccurrent is proportional to the degree of applanation.

[0788] Preferably, the electrical circuit utilized by the applanationsensor D2 is identical or similar to that used by the alignment sensorD1.

[0789] The electric signal indicative of the area of applanation canthen be combined with signals indicative of the time it takes to achievesuch applanation and/or the amount of current (which, in turn,corresponds to the applied force) used to achieve the applanation, andthis combination of information can be used to determine the intraocularpressure using the equation Pressure=Force/Area.

[0790] The following are preferred operational steps for the actuationapparatus during a measurement cycle:

[0791] 1) While the actuation apparatus is OFF, there is no magneticfield being directed toward the contact device 2.

[0792] 2) When the actuation apparatus is turned ON, the magnetic fieldinitially remains at zero.

[0793] 3) Once the patient is in position, the patient starts to alignhis/her eye with the actuation apparatus. Until the eye is properlyaligned, the magnetic field remains zero.

[0794] 4) When the eye is properly aligned (as automatically sensed bythe optical alignment Sensor), the magnetic field (driven by a steadilyincreasing electric current) starts to increase from zero.

[0795] 5) During the time period of the current increase (approximately0.01 sec.), the force on the movable central piece also increasessteadily.

[0796] 6) In response to the increasing force on the movable centralpiece, the surface area of the cornea adjacent to the movable centralpiece is increasingly flattened.

[0797] 7) Light from the flattened surface area of the cornea isreflected toward the detecting arrangement which detects when apredetermined amount of applanation has been achieved. Since the amountof light reflected straight back from the cornea is proportional to thesize of the flattened surface area, it is possible to determine exactlywhen the predetermined amount of applanation has been achieved,preferably a circular area of diameter 3.1 mm, of the cornea. It isunderstood, however, that any diameter ranging from 0.10 mm to 10 mm canbe utilized.

[0798] 8) The time required to achieve applanation of the particularsurface area (i.e, the predetermined amount of applanation) is detectedby a timing circuit which is part of the applanation detectingarrangement. Based on prior calibration and a resulting conversiontable, this time is converted to an indication of intraocular pressure.The longer the time required to applanate a specific area, the higherthe intraocular pressure, and vice versa.

[0799] 9) After the predetermined amount of applanation is achieved, themagnetic field is turned OFF.

[0800] 10) The intraocular pressure is then displayed by a readoutmeter, and all circuits are preferably turned completely OFF for aperiod of 15 seconds so that the automatic measurement cycle will not beimmediately repeated if the patient's eye remains aligned. It isunderstood, however, that the circuits may remain ON and that acontinuous measurement of intraocular pressure may be achieved bycreating an automatic measurement cycle. The data provided by thisautomatic measurement cycle then may be used to calculate blood flow.

[0801] 11) If the main power supply has not been turned OFF, allcircuits are turned back ON after 15 seconds and thus become ready forthe next measurement.

[0802] Although there are several methods for calibrating the variouselements of the system for measuring intraocular pressure byapplanation, the following are illustrative examples of how suchcalibration can be achieved:

[0803] Initially, after manufacturing the various components, eachcomponent is tested to ensure the component operates properly. Thispreferably includes verifying that there is free piston-like movement(no twisting) of the movable central piece in the contact device;verifying the structural integrity of the contact device during routinehandling; evaluating the magnetic field at the surface of the movablecentral piece in order to determine its magnetic dipole moment (whenmagnetic actuation is utilized); verifying that the electrical currentpulse which creates the magnetic field that actuates the magneticallyresponsive element of the movable central piece, has an appropriate peakmagnitude and duration, and ensuring that there is no “ringing”;verfying the efficacy of the “demagnetization circuit” at removing anyresidual magnetization in the iron-core of the actuation apparatus afterit has been pulsed; measuring the magnetic field as a function of timealong and near the longitudinal axis of the coil where the movablecentral piece will eventually be placed; determining and plotting grad Bas a function of time at several x-locations (i.e., at several distancesfrom the coil); and positioning the magnetic central piece (contactdevice) at several x-locations along the coil's longitudinal axis anddetermining the force F acting on it as a function of time duringpulsed-operation of the actuation apparatus.

[0804] Next, the optical alignment system is tested for properoperation. When the optical alignment system comprises the arrangementillustrated in FIGS. 16 and 17, for example, the following testing andcalibration procedure may be used:

[0805] a) First, a convex glass surface (one face of a lens) having aradius of curvature approximately the same as that of the cornea is usedto simulate the cornea and its surface reflection. Preferably, thisglass surface is placed in a micrometer-adjusted mounting arrangementalong the longitudinal axis of the coil. The micrometer-adjustedmounting arrangement permits rotation about two axes (tip & tilt) andtranslation in three-dimensional x-y-z space.

[0806] b) With the detector D1 connected to a voltage or current meter,the convex glass surface located at its design distance of 25 mm fromlens L4 will be perfectly aligned (tip/tilt/x/y/z) by maximizing theoutput signal at the read-out meter.

[0807] c) After perfect alignment is achieved, the alignment detectionarrangement is “detuned” for each of the positional degrees of freedom(tip/tilt/x/y/z) and curves are plotted for each degree of freedom tothereby define the system's sensitivity to alignment.

[0808] d) The sensitivity to alignment will be compared to the desiredtolerances in the reproducibility of measurements and also can be basedon the variance of the magnetic force on the movable central piece as afunction of position.

[0809] e) Thereafter, the sensitivity of the alignment system can bechanged as needed by such procedures as changing the size of theaperture in the silicon photodiode which functions as the alignmentsensor D1, and/or changing an aperture stop at lens L4.

[0810] Next, the detection arrangement is tested for proper operation.When the detection arrangement comprises the optical detectionarrangement illustrated in FIG. 16, for example, the following testingand calibration procedure may be used:

[0811] a) A flat glass surface (e.g., one face of a short polished rod)with a diameter of preferably 4-5 mm is used to simulate the applanatedcornea and its surface reflection.

[0812] b) A black, opaque aperture defining mechanism (which definesclear inner apertures with diameters ranging from 0.5 to 4 mm and whichhas an outer diameter the same as that of the rod) is arranged so as topartially cover the face of the rod, thus simulating various stages ofapplanation.

[0813] c) The flat surfaced rod is placed in a mount along thelongitudinal axis of the coil in a micrometer-adjusted mountingarrangement that can rotate about two axes (tip & tilt) and translate inthree-dimensional x-y-z space.

[0814] d) The applanation sensor D2 is then connected to a voltage orcurrent meter, while the rod remains located at its design distance of25 mm from the lens L4 where it is perfectly aligned (tip/tilt/x/y/z) bymaximizing the output signal from the applanation sensor D2. Alignment,in this case, is not sensitive to x-axis positioning.

[0815] e) After perfect alignment is achieved, the alignment is“detuned” for each of the positional degrees of freedom (tip/tilt/x/y/z)and curves are plotted for each degree of freedom thus defining thesystem's sensitivity to alignment. Data of this kind is obtained for thevariously sized apertures (i.e. different degrees of applanation) at theface of the rod.

[0816] f) The sensitivity to alignment is then compared to thetolerances required for reproducing applanation measurements whichdepends, in part, on the results obtained in the aforementioned testingand calibration method associated with the alignment apparatus.

[0817] g) The sensitivity of the applanation detecting arrangement isthen changed as needed by such procedures as changing the size of theaperture in front of the applanation sensor D2 and/or changing theaperture stop (small hole) at the beam splitter BS2.

[0818] Further calibration and in-vitro measurements can be carried outas follows: After the aforementioned calibration and testing procedureshave been carried out on the individual subassemblies, all parts can becombined and the system tested as an integrated unit. For this purpose,ten enucleated animal eyes and ten enucleated human eyes are measured intwo separate series. The procedures for both eye types are the same. Theeyes are mounted in non-magnetic holders, each having a central openingwhich exposes the cornea and part of the sclera. A 23 gauge needleattached to a short piece of polyethylene tubing is then inserted behindthe limbus through the sclera and ciliary body and advanced so that thetip passes between the lens and iris. Side ports are drilled in thecannulas about 2 mm from the tip to help avoid blockage of the cannulaby the iris or lens. This cannula is attached to a pressure transducerwith an appropriate display element. A normal saline reservoir ofadjustable height is also connected to the pressure transducer tubingsystem. The hydrostatic pressure applied to the eye by this reservoir isadjustable between 0 and 50 mm Hg, and intraocular pressure over thisrange can be measured directly with the pressure transducer.

[0819] In order to verify that the foregoing equipment is properly setup for each new eye, a standard Goldman applanation tonometer can beused to independently measure the eye's intraocular pressure at a singleheight of the reservoir. The intraocular value measured using theGoldman system is then compared to a simultaneously determinedintraocular pressure measured by the pressure transducer. Any problemsencountered with the equipment can be corrected if the two measurementsare significantly different.

[0820] The reservoir is used to change in 5 mm Hg sequential steps theintraocular pressure of each eye over a range of pressures from 5 to 50mm Hg. At each of the pressures, a measurement is taken using the systemof the present invention. Each measurement taken by the presentinvention consists of recording three separate time-varying signals overthe time duration of the pulsed magnetic field. The three signalsare: 1) the current flowing in the coil of the actuation apparatus as afunction of time, labelled I (t), 2) the voltage signal as a function oftime from the applanation detector D2, labelled APPLN (t), and 3) thevoltage signal as a function of time from the alignment sensor D1,labelled ALIGN (t). The three signals, associated with each measurement,are then acquired and stored in a computer equipped with a multi-input“data acquisition and processing” board and related software.

[0821] The computer allows many things to be done with the dataincluding: 1) recording and storing many signals for subsequentretrieval, 2) displaying graphs of the signals versus time, 3) numericalprocessing and analyses in any way that is desired, 4) plotting finalresults, 5) applying statistical analyses to groups of data, and 6)labeling the data (e.g. tagging a measurement set with its associatedintraocular pressure).

[0822] The relationship between the three time-varying signals andintraocular pressure are as follows:

[0823] 1. I(t) is an independent input signal which is consistentlyapplied as current pulse from the power supply which activates theactuation apparatus. This signal I (t) is essentially constant from onemeasurement to another except for minor shot-to-shot variations. I (t)is a “reference” waveform against which the other waveforms, APPLN (t)and ALIGN (t) are compared as discussed further below.

[0824] 2. APPLN(t) is a dependent output signal. APPLN(t) has a value ofzero when I(t) is zero (i.e. at the very beginning of the current pulsein the coil of the actuation apparatus. The reason for this is that whenI=0, there is no magnetic field and, consequently, no applanation forceon the movable central piece. As I (t) increases, so does the extent ofapplanation and, correspondingly, so does APPLN(t). It is important tonote that the rate at which APPLN(t) increases with increasing I(t)depends on the eye's intraocular pressure. Since eyes with lowintraocular pressures applanate more easily than eyes with highintraocular pressures in response to an applanation force, it isunderstood that APPLN(t) increases more rapidly for an eye having a lowintraocular pressure than it does for an eye having a high intraocularpressure. Thus, APPLN (t) increases from zero at a rate that isinversely proportional to the intraocular pressure until it reaches amaximum value when full applanation is achieved.

[0825] 3. ALIGN(t) is also a dependent output signal. Assuming an eye isaligned in the setup, the signal ALIGN(t) starts at some maximum valuewhen I(t) is zero (i.e. at the very beginning of the current pulse tothe coil of the actuation apparatus). The reason for this is that whenI=0, there is no magnetic field and, consequently, no force on themovable central piece which would otherwise tend to alter the cornea'scurvature. Since corneal reflection is what gives rise to the alignmentsignal, as I(t) increases causing applanation (and, correspondingly, adecrease in the extent of corneal curvature), the signal ALIGN (t)decreases until it reaches zero at full applanation. It is important tonote that the rate at which ALIGN (t) decreases with increasing I(t)depends on the eye's intraocular pressure. Since extraocular pressureapplanate more easily than eyes with high intraocular pressure, it isunderstood that ALIGN (t) decreases more rapidly for an eye having a lowintraocular pressure than for an eye having a high intraocular pressure.Thus, ALIGN(t) decreases from some maximum value at a rate that isinversely proportional to the intraocular pressure until it reaches zerowhen full applanation is achieved.

[0826] From the foregoing, it is clear that the rate of change of bothoutput signals, APPLN and ALIGN, in relation to the input signal I isinversely proportional to the intraocular pressure. Therefore, themeasurement of intraocular pressure using the present invention maydepend on determining the SLOPE of the AAPPLN versus I@ measurement data(also, although probably with less certainty, the slope of the “ALIGNversus I” measurement data).

[0827] For the sake of brevity, the following description is limited tothe “APPLN versus I” data; however, it is understood that the “ALIGNversus I” data can be processed in a similar manner.

[0828] Plots of AAPPLN versus I@ can be displayed on the computermonitor for the various measurements (all the different intraocularpressures for each and every eye) and regression analysis (and otherdata reduction algorithms) can be employed in order to obtain the “bestfit” SLOPE for each measurement. Time can be spent in order to optimizethis data reduction procedure. The end result of a series of pressuremeasurements at different intraocular pressures on an eye (determined bythe aforementioned pressure transducer) will be a corresponding seriesof SLOPE's (determined by the system of the present invention).

[0829] Next, a single plot is prepared for each eye showing SLOPE versusintraocular pressure data points as well as a best fitting curve throughthe data. Ideally, all curves for the 10 pig eyes are perfectlycoincident—with the same being true for the curves obtained for the 10human eyes. If the ideal is realized, any of the curves can be utilized(since they all are the same) as a CALIBRATION for the presentinvention. In practice, however, the ideal is probably not realized.

[0830] Therefore, all of the SLOPE versus intraocular pressure data forthe 10 pig eyes is superimposed on a single plot (likewise for the SLOPEversus intraocular pressure data for the 10 human eyes). Suchsuperimposing generally yields an “averaged” CALIBRATION curve, and alsoindication of the reliability associated with the CALIBRATION.

[0831] Next, the data in the single plots can be analyzed statistically(one for pig eyes and one for human eyes) which, in turn, shows acomposite of all the SLOPE versus intraocular pressure data. From thestatistical analysis, it is possible to obtain: 1) an averagedCALIBRATION curve for the present invention from which one can obtainthe A most likely intraocular pressure” associated with a measured SLOPEvalue, 2) the Standard Deviation (or Variance) associated with anyintraocular pressure determination made using the present invention,essentially the present invention's expected “ability” to replicatemeasurements, and 3) the “reliability” or “accuracy” of the presentinvention's CALIBRATION curve which is found from a“standard-error-of-the mean” analysis of the data.

[0832] In addition to data obtained with the eyes aligned, it is alsopossible to investigate the sensitivity of intraocular pressuremeasurements made using the present invention, to translational androtational misalignment.

Alternative Embodiment for Measuring Intraocular Pressure by Indentation

[0833] With reference to FIGS. 20A and 20B, an alternative embodimentfor measuring intraocular pressure by indentation will now be described.

[0834] The alternative embodiment includes an indentation distancedetection arrangement and contact device. The contact device has amovable central piece 16 of which only the outside surface isillustrated in FIGS. 20A and 20B. The outside surface of the movablecentral piece 16 is at least partially reflective.

[0835] The indentation distance detection arrangement includes twoconverging lenses L1 and L2; a beam splitter BS1; a light source LS foremitting a beam of light having a width w; and a light detector LDresponsive to the diameter of a reflected beam impinging on a surfacethereof.

[0836]FIG. 20A illustrates the alternative embodiment prior to actuationof the movable central piece 16. Prior to actuation, the patient isaligned with the indentation distance detection arrangement so that theouter surface of the movable central piece 16 is located at the focalpoint of the converging lens L2. When the movable central piece 16 is solocated, the beam of light from the light source LS strikes the beamsplitter BS and is deflected through the converging lens L1 to impingeas a point on the reflective outer surface of the movable central piece16. The reflective outer surface of the movable central piece 16 thenreflects this beam of light back through the converging lens L1, throughthe beam splitter BS, and then through the converging lens L2 to strikea surface of the light detector LD. Preferably, the light detector LD islocated at the focal point of the converging lens L2 so that thereflected beam impinges on a surface of the light detector LD as a pointof virtually zero diameter when the outer surface of the movable centralpiece remains at the focal point of the converging lens L1.

[0837] Preferably, the indentation distance detection arrangement isconnected to a display device so as to generate an indication of zerodisplacement when the outer surface of the movable central piece 16 hasyet to be displaced, as shown in FIG. 20A.

[0838] By subsequently actuating the movable central piece 16 using anactuating device (preferably, similar to the actuating devices describedabove), the outer surface of the movable central piece 16 movesprogressively away from the focal point of the converging lens L1, asillustrated in FIG. 20B. As a result, the light beam impinging on thereflective outer surface of the movable central piece 16 has aprogressively increasing diameter. This progressive increase in diameteris proportional to the displacement from the focal point of theconverging lens L1. The resulting reflected beam therefore has adiameter proportional to the displacement and passes back through theconverging lens L1, through the beam splitter BS, through the converginglens C2 and then strikes the surface of the light detector LD with adiameter proportional to the displacement of the movable central piece16. Since the light detector LD is responsive, as indicated above, tothe diameter of the reflected light beam, any displacement of themovable central piece 16 causes a proportional change in output from thelight detector LD.

[0839] Preferably, the light detector LD is a photoelectric converterconnected to the aforementioned display device and capable of providingan output voltage proportional to the diameter of the reflected lightbeam impinging upon the light detector LD. The display device thereforeprovides a visual indication of displacement based on the output voltagefrom the light detector LD.

[0840] Alternatively, the output from the light detector LD may beconnected to an arrangement, as described above, for providing anindication of intraocular pressure based on the displacement of themovable central piece 16.

Additional Capabilities

[0841] Generally, the present apparatus and method makes it possible toevaluate intraocular pressure, as indicated above, as well as ocularrigidity, eye hydrodynamics such as outflow facility and inflow rate ofeye fluid, eye hemodynamics such as the pressure in the episoleral veinsand the pulsatile ocular blood flow, and has also the ability toartificially increase intraocular pressure, as well as the continuousrecording of intraocular pressure.

[0842] With regard to the measurement of intraocular pressure byapplanation, the foregoing description sets forth several techniques foraccomplishing such measurement, including a variable force techniquewherein the force applied against the cornea varies with time. It isunderstood, however, that a variable area method can also beimplemented.

[0843] The apparatus can evaluate the amount of area applanated by aknown force. The pressure is calculated by dividing the force by theamount of area that is applanated. The amount of area applanated isdetermined using the optical means and/or filters previously described.

[0844] A force equivalent to placing 5 gram of weight on the cornea, forexample, will applanate a first area if the pressure is 30 mmHg, asecond area if the pressure is 20 mmHg, a third area if the pressure is15 mmHg and so on. The area applanated is therefore indicative ofintraocular pressure.

[0845] Alternatively, intraocular pressure can be measured using anon-rigid interface and general applanation techniques. In thisembodiment, a flexible central piece enclosed by the magnet of themovable central piece is used and the transparent part of the movablecentral piece acts like a micro-balloon. This method is based on theprinciple that the interface between two spherical balloons of unequalradius will be flat if the pressures in the two balloons are equal. Thecentral piece with the balloon is pressed against the eye until theeye/central piece interface is planar as determined by theaforementioned optical means.

[0846] Also, with regard to the previously described arrangement whichmeasures intraocular pressure by indentation, an alternative method canbe implemented with such an embodiment wherein the apparatus measuresthe force required to indent the cornea by a predetermined amount. Thisamount of indentation is determined by optical means as previouslydescribed. The movable central piece is pressed against the cornea toindent the cornea, for example, 0.5 mm (though it is understood thatvirtually any other depth can be used). Achievement of the predetermineddepth is detected by the previously described optical means and filters.According to tables, the intraocular pressure can be determinedthereafter from the force.

[0847] Yet another technique which the present invention facilitates useof is the ballistic principle. According to the ballistic principle, aparameter of a collision between the known mass of the movable centralpiece and the cornea is measured. This measured parameter is thenrelated theoretically or experimentally to the intraocular pressure. Thefollowing are exemplary parameters:

[0848] Impact Acceleration

[0849] The movable central piece is directed at the cornea at a welldefined velocity. It collides with the cornea and, after a certain timeof contact, bounces back. The time-velocity relationships during andafter impact can be studied. The applanating central piece may have aspring connecting to the rigid annular member of the contact device. Ifthe corneal surface is hard, the impact time will be short. Likewise, ifthe corneal surface is soft the impact time will be longer. Opticalsensors can detect optically the duration of impact and how long ittakes for the movable central piece to return to its original position.

[0850] Impact Duration

[0851] Intraocular pressure may also be estimated by measuring theduration of contact of a spring driven movable central piece with theeye. The amount of time that the cornea remains flattened can beevaluated by the previously described optical means.

[0852] Rebound Velocity

[0853] The distance traveled per unit of time after bouncing is alsoindicative of the rebound energy and this energy is proportional tointraocular pressure.

[0854] Vibration Principle

[0855] The intraocular pressure also can be estimated by measuring thefrequency of a vibrating element in contact with the contact device andthe resulting changes in light reflection are related to the pressure inthe eye.

[0856] Time

[0857] The apparatus of the present invention can also be used, asindicated above, to measure the time that it takes to applanate thecornea. The harder the cornea, the higher the intraocular pressure andthus the longer it takes to deform the cornea. On the other hand, thesofter the cornea, the lower the intraocular pressure and thus theshorter it takes to deform the cornea. Thus, the amount of time that ittakes to deform the cornea is proportional to the intraocular pressure.

[0858] Additional uses and capabilities of the present invention relateto alternative methods of measuring outflow facility (tonography). Thesealternative methods include the use of conventional indentationtechniques, constant depth indentation techniques, constant pressureindentation techniques, constant pressure applanation techniques,constant area applanation techniques, and constant force applanationtechniques.

[0859] 1. Conventional Indentation

[0860] When conventional indentation techniques are utilized, themovable central piece of the present invention is used to indent thecornea and thereby artificially increase the intraocular pressure. Thisartificial increase in intraocular pressure forces fluid out of the eyemore rapidly than normal. As fluid leaves the eye, the pressuregradually returns to its original level. The rate at which theintraocular pressure falls depends on how well the eye's drainage systemis functioning. The drop in pressure as a function of time is used tocalculated the C value or coefficient of outflow facility. The C valueis indicative of the degree to which a change in intraocular pressurewill cause a change in the rate of fluid outflow. This, in turn, isindicative of the resistance to outflow provided by the eye's drainagesystem. The various procedures for determining outflow facility aregenerally known as tonography and the C value is typically expressed interms of microliters per minute per millimeter of mercury. The C valueis determined by raising the intraocular pressure using the movablecentral piece of the contact device and observing the subsequent decayin intraocular pressure with respect to time. The elevated intraocularpressure increases the rate of aqueous outflow which, in turn, providesa change in volume. This change in volume can be calculated from theFriedenwald tables which correlate volume change to pressure changes.The rate of volume decrease equals the rate of outflow. The change inintraocular pressure during the tonographic procedure can be computed asan arithmetical average of pressure increments for successive 2 minuteintervals. The C value is derived then from the following equation:C=ΔV/t*(Pave−Po), in which t is the duration of the procedure, Pave isthe average pressure elevation during the test and can be measured, Pois the initial pressure and it is also measured, and ΔV is differencebetween the initial and final volumes and can be obtained from knowntables. The Flow (AF@) of fluid is then calculated using the formula:F=C*(Po−Pv), in which Pv is the pressure in the episcleral veins whichcan be measured and generally has a constant value of 10.

[0861] 2. Constant Depth Indentation

[0862] When constant depth indentation techniques are utilized, themethod involves the use of a variable force which is necessary to causea certain predetermined amount of indentation in the eye. The apparatusof the present invention is therefore configured so as to measure theforce required to indent the cornea by a predetermined amount. Thisamount of indentation may be detected using optical means as previouslydescribed. The movable central piece is pressed against the cornea toindent the eye, for example, by approximately 0.5 mm. The amount ofindentation is detected by the optical means and filters previouslydescribed. With the central piece indenting the cornea using a forceequivalent to a weight of 10 grams, a 0.5 mm indentation will beachieved under normal pressure conditions (e.g., intraocular pressure of15 mm Hg) and assuming there is an average corneal curvature. With thatamount of indentation and using standard dimensions for the centralpiece, 2.5 mm³ of fluid will be displaced. The force recorded by thepresent invention undergoes a slow decline and it levels off at a moreor less steady state value after 2 to 4 minutes. The decay in pressureis measured based on the difference between the value of the firstindentation of the central piece and the final level achieved after acertain amount of time. The pressure drop is due to the return ofpressure to its normal value, after it has been artificially raised bythe indentation caused by the movable central piece. A known normalvalue of decay is used as a reference and is compared to the valuesobtained. Since the foregoing provides a continuous recording ofpressure over time, this method can be an important tool forphysiological research by showing, for example, an increase in pressureduring forced expiration. The pulse wave and pulse amplitude can also beevaluated and the pulsatile blood flow calculated.

[0863] 3. Constant Pressure Indentation

[0864] When constant pressure indentation techniques are utilized, theintraocular pressure is kept constant by increasing the magnetic fieldand thereby increasing the force against the cornea as fluid leaks outof the eye. At any constant pressure, the force and rate of outflow arelinearly related according to the Friedenwald tonometry tables. Theintraocular pressure is calculated using the same method as describedfor conventional indentation tonometry. The volume displacement iscalculated using the tonometry tables. The facility of outflow (C) maybe computed using two different techniques. According to the firsttechnique, C can be calculated from two constant pressure tonograms atdifferent pressures according to the equation,C={[(ΔV₁/t₁)−(ΔV₂/t₂)]/(P₁−P₂)}, in which 1 corresponds to a measurementat a first pressure and 2 corresponds to a measurement at a secondpressure (which is higher than the first pressure). The second way tocalculate C is from one constant pressure tonogram and an independentmeasure of intraocular pressure using applanation tonometry (P_(a)), inC=[(ΔV/t)/(P−P_(a)−ΔP_(e))], where ΔP_(e) is a correction factor forrise in episcleral venous pressure with indentation tonometry and P isthe intraocular pressure obtained using indentation tonometry.

[0865] 4. Constant Pressure Applanation

[0866] When constant pressure applanation techniques are utilized, theintraocular pressure is kept constant by increasing the magnetic fieldand thus the force as fluid leaks out of the eye. If the cornea isconsidered to be a portion of a sphere, a mathematical formula relatesthe volume of a spherical segment to the radius of curvature of thesphere and the radius of the base of the segment. The volume displacedis calculated based on the formula V=A²/(4*π*R), in which V is volume, Ais the area of the segment base, and R is the radius of curvature of thesphere (this is the radius of curvature of the cornea). SinceA=weight/pressure, then V=W²/(4*π*R*P²). The weight is constituted bythe force in the electromagnetic field, R is the curvature of the corneaand can be measured with a keratometer, P is the pressure in the eye andcan be measured using the same method as described for conventionalapplanation tonometry. It is therefore possible to calculate the volumedisplaced and the C value or outflow facility. The volume displaced, forexample, can be calculated at 15 second intervals and is plotted as afunction of time.

[0867] 5. Constant Area Applanation

[0868] When constant area applanation techniques are utilized, themethod consists primarily of evaluating the pressure decay curve whilethe flattened area remains constant. The aforementioned opticalapplanation detecting arrangements can be used in order to keep constantthe area flattened by the movable central piece. The amount of forcenecessary to keep the flattened area constant decreases and thisdecrease is registered. The amount of volume displaced according to thedifferent areas of applanation is known. For instance, a 5 mmapplanating central piece displaces 4.07 mm of volume for the averagecorneal radius of 7.8 mm. Using the formula ΔV/Δt=1/(R*ΔP), it ispossible to calculate R which is the reciprocal of C. Since a continuousrecording of pressure over time is provided, this method can be animportant tool for research and evaluation of blood flow.

[0869] 6. Constant Force Applanation

[0870] When constant force applanation techniques are utilized, the sameforce is constantly applied and the applanated area is measured usingany of the aforementioned optical applanation detection arrangements.Once the area flattened by a known force is measured, the pressure canbe calculated by dividing the force by the amount of area that isapplanated. As fluid leaves the eye the amount of area applanatedincreases with time. This method consists primarily of evaluating aresulting area augmentation curve while the constant force is applied.The amount of volume displaced according to the different areas ofapplanation is known. Using the formula ΔV/Δt=1/(R*ΔP), it is possibleto calculate R which is the reciprocal of C.

[0871] Still additional uses of the present invention relate todetecting the frequency response of the eye, using indentationtonometry. In particular, if an oscillating force is applied using themovable central piece 16, the velocity of the movable central piece 16is indicative of the eye's frequency response. The system oscillates atthe resonant frequency determined primarily by the mass of the movablecentral piece 16. By varying the frequency of the force and by measuringthe response, the intraocular pressure can be evaluated. The evaluationcan be made by measuring the resonant frequency and a significantvariation in resonant frequency can be obtained as a function of theintraocular pressure.

[0872] The present invention may also be used with the foregoingconventional indentation techniques, but where the intraocular pressureused for calculation is measured using applanation principles. Sinceapplanation virtually does not disturb the hydrodynamic equilibriumbecause it displaces a very small volume, this method can be consideredmore accurate than intraocular pressure measurements made usingtraditional indentation techniques.

[0873] Another use of the present invention involves a time related wayof measuring the resistance to outflow. In particular, the resistance tooutflow is detected by-measuring the amount of time necessary totransfigure the cornea with either applanation or indentation. The timenecessary to displace, for example, 5 microliters of eye fluid would be1 second for normal patients and above 2 seconds for glaucoma-strickenindividuals.

[0874] Yet another use of the present invention involves measuring theinflow of eye fluid. In particular, this measurement is made by applyingthe formula F=ΔP/R, in which ΔP is P−P_(v), and P is the steady stateintraocular pressure and P_(v) is the episeleral venous pressure which,for purposes of calculation, is considered constant at 10. R is theresistance to outflow, which is the reciprocal of C that can becalculated. F, in units of volume/min, can then be calculated.

[0875] The present invention is also useful at measuring ocularrigidity, or the distensibility of the eye in response to an increasedintraocular pressure. The coefficient of ocular rigidity can becalculated using a nomogram which is based on two tonometric readingswith different weights. A series of conversion tables to calculate thecoefficient of ocular rigidity was developed by Friedenwald. Thetechnique for determining ocular rigidity is based on the concept ofdifferential tonometry, using two indentation tonometric readings withdifferent weights or more accurately, using one indentation reading andone applanation reading and plotting these readings on the nomogram.Since the present invention can be used to measure intraocular pressureusing both applanation and indentation techniques, a more accurateevaluation of the ocular rigidity can be achieved.

[0876] Measurements of intraocular pressure using the apparatus of thepresent invention can also be used to evaluate hemodynamics, inparticular, eye hemodynamics and pulsatile ocular blood flow. Thepulsatile ocular blood flow is the component of the total oculararterial inflow that causes a rhythmic fluctuation of the intraocularpressure. The intraocular pressure varies with each pulse due to thepulsatile influx of a bolus of arterial blood into the eye with eachheartbeat. This bolus of blood enters the intraocular arteries with eachheartbeat causing a temporary increase in the intraocular pressure. Theperiod of inflow causes a stretching of the eye walls with a concomitantincrease in pressure followed by a relaxation to the previous volume anda return to the previous pressure as the blood drains from the eye. Ifthis process of expansion during systole (contraction of the heart) andcontraction during diastole (relaxation of the heart) occurs at acertain pulse rate, then the blood flow rate would be the incrementalchange in eye volume times the pulse rate.

[0877] The fact that intraocular pressure varies with time according tothe cardiac cycle is the basis for measuring pulsatile ocular bloodflow. The cardiac cycle is approximately in the order of 0.8 Hz. Thepresent invention can measure the time variations of intraocularpressure with a frequency that is above the fundamental human heart beatfrequency allowing the evaluation and recording of intraocular pulse. Inthe normal human eye, the intraocular pulse has a magnitude ofapproximately 3 mm Hg and is practically synchronous with the cardiaccycle.

[0878] As described, measurements of intraocular pressure show a timevariation that is associated with the pulsatile component of arterialpressure. Experimental results provide means of transforming ocularpressure changes into eye volume changes. Each bolus of blood enteringthe eye increases the ocular volume and the intraocular pressure. Theobserved changes in pressure reflect the fact that the eye volume mustchange to accommodate changes in the intraocular blood volume induced bythe arterial blood pulse. This pulse volume is small relative to theocular volume, but because the walls of the eye are stiff, the pressureincrease required to accommodate the pulse volume is significant and canbe measured. Therefore, provided that the relationship between theincreased intraocular pressure and increased ocular volume is known, thevolume of the bolus of fluid can be determined. Since this relationshipbetween pressure change and volume change has been well established(Friedenwald 1937, McBain 1957, Ytteborg 1960, Eisenlohr 1962, McEwen1965), the pressure measurements can be used to obtain the volume of abolus of blood and thereby determine the blood flow.

[0879] The output of the tonometer for the instantaneous pressure can beconverted into instantaneous change in eye volume as a function of time.The time derivative of the change in ocular volume is the netinstantaneous pulsatile component of the ocular blood flow. Under theseconditions, the rate of pulsatile blood flow through the eye can be.evaluated from the instantaneous measurement of intraocular pressure. Inorder to rapidly quantify and analyze the intraocular pulse, the signalfrom the tonometer may be digitalized and fed into a computer.

[0880] Moreover, measurements of intraocular pressure can be used toobtain the intraocular volume through the use of an independentlydetermined pressure-volume relationship such as with the Friedenwaldequation (Friedenwald, 1937). A mathematical model based on experimentaldata from the pressure volume relationship (Friedenwald 1937, McBain1957, Eisenlohr 1962, McEwen 1965) can also be used to convert a changein ocular pressure into a change in ocular volume.

[0881] In addition, a model can also be constructed to estimate theocular blood flow from the appearance of the intraocular pressurewaveform. The flow curve is related to parameters that come from thevolume change curve. This curve is indirectly measured since theintraocular pressure is the actual measured quantity which istransformed into volume change through the use of the measuredpressure-volume relation. The flow is then computed by taking the changein volume Vmax−Vmin multiplied by a constant that is related to thelength of the time interval of the inflow and the total pulse length.Known mathematical calculations can be used to evaluate the pulsatilecomponent of the ocular blood flow. Since the present invention can alsobe used to measure the ocular rigidity, this parameter of coefficient ofocular rigidity can be used in order to more precisely calculateindividual differences in pulsatile blood flow.

[0882] Moreover, since the actuation apparatus 6 and contact device 2 ofthe present invention preferably include transparent portions, thepulsatile blood flow can be directly evaluated optically to quantify thechange in size of the vessels with each heart beat. A more preciseevaluation of blood flow therefore can be achieved by combining thechanges in intraocular pulse with changes in vessel diameter which canbe automatically measured optically.

[0883] A vast amount of data about the vascular system of the eye andcentral nervous system can be obtained after knowing the changes inintraocular pressure over time and the amount of pulsatile ocular bloodflow. The intraocular pressure and intraocular pulse are normallysymmetrical in pairs of eyes. Consequently, a loss of symmetry may serveas an early sign of ocular or cerebrovascular disease. Patientsafflicted with diabetes, macular degeneration, and other vasculardisorders may also have a decreased ocular blood flow and benefit fromevaluation of eye hemodynamics using the apparatus of the presentinvention.

[0884] The present invention may also be used to artificially elevateintraocular pressure. The artificial elevation of intraocular pressureis an important tool in the diagnosis and prognosis of eye and braindisorders as well as an important tool for research.

[0885] Artificial elevation of intraocular pressure using the presentinvention can be accomplished in different ways. According to one way,the contact device of the present invention is modified in shape forplacement on the sclera (white of the eye). This arrangement, which willbe described hereinafter, is illustrated in FIGS. 21-22, wherein themovable central piece 16 may be larger in size and is preferablyactuated against the sclera in order to elevate the intraocularpressure. The amount of indentation can be detected by the opticaldetection system previously described.

[0886] Another way of artificially increasing the intraocular pressureis by placing the contact device of the present invention on the corneain the same way as previously described, but using the movable centralpiece to apply a greater amount of force to achieve deeper indentation.This technique advantageously allows visualization of the eye whileexerting the force, since the movable central portion of the contactdevice is preferably transparent. According to this technique, the sizeof the movable central piece can also be increased to indent a largerarea and thus create a higher artificial increase of intraocularpressure. Preferably, the actuation apparatus also has a transparentcentral portion, as indicated above, to facilitate direct visualizationof the eye and retina while the intraocular pressure is being increased.When the intraocular pressure exceeds the ophthalmic arterial diastolicpressure, the pulse amplitude and blood flow decreases rapidly. Bloodflow becomes zero when the intraocular pressure is equal or higher thanthe ophthalmic systolic pressure. Thus, by allowing direct visualizationof the retinal vessels, one is able to determine the exact moment thatthe pulse disappears and measure the pressure necessary to promote thecessation of the pulse which, in turn, is the equivalent of the pulsepressure in the ophthalmic artery. The present invention thus allows themeasurement of the pressure in the arteries of the eye.

[0887] Also, by placing a fixation light in a back portion of theactuation apparatus and asking the patient to indicate when he/she canno longer see the light, one can also record the pressure at which apatient's vision ceases. This also would correspond to the cessation ofthe pulse in the artery of the eye. The pressure in which vessels opencan also be determined by increasing intraocular pressure until thepulse disappears and then gradually decreasing the intraocular pressureuntil the pulse reappears. Thus, the intraocular pressure necessary forvessels to open can be evaluated.

[0888] It is important to note that the foregoing measurements can beperformed automatically using an optical detection system, for example,by aiming a light beam at the pulsating blood vessel. The cessation ofpulsation can be optically recognized and the pressure recorded. Anattenuation of pulsations can also be used as the end point and can beoptically detected. The apparatus also allows direct visualization ofthe papilla of the optic nerve while an increased intraocular pressureis produced. Thus, physical and chemical changes occurring inside theeye due to the artificial increase in intraocular pressure may beevaluated at the same time that pressure is measured.

[0889] Advantageously, the foregoing, test can be performed on patientswith media opacities that prevent visualization of the back of the eye.In particular, the aforementioned procedure wherein the patientindicates when vision ceases is particular useful in patients with mediaopacities. The fading of the peripheral vision corresponds to thediastolic pressure and fading of the central vision corresponds to thesystolic pressure.

[0890] The present invention, by elevating the intraocular pressure, asindicated above and by allowing direct visualization of blood vessels inthe back of the eye, may be used for tamponade (blockade of bleeding byindirect application of pressure) of hemorrhagic processes such as thosewhich occur, for example, in diabetes and macular degeneration. Theelevation of intraocular pressure may also be beneficial in thetreatment of retinal detachments.

[0891] As yet another use of the present invention, the aforementionedapparatus also can be used to measure outflow pressure of the eye fluid.In order to measure outflow pressure in the eye fluid, the contactdevice is placed on the cornea and a measurable pressure is applied tothe cornea. The pressure causes the aqueous vein to increase in diameterwhen the pressure in the cornea equals the outflow pressure. Thepressure on the cornea is proportional to the outflow pressure. The flowof eye fluid out of the eye is regulated according to Poiseuille's Lawfor laminar currents. If resistance is inserted into the formula, theresult is a formula similar to Ohm's Law. Using these known formulas,the rate of flow (volume per time) can be determined. The change in thediameter of the vessel which is the reference point can be detectedmanually by direct observation and visualization of the change indiameter or can be done automatically using an optical detection systemcapable of detecting a change in reflectivity due to the amount of fluidin the vein and the change in the surface area. The actual cross-sectionof the vein can be detected using an optical detection system.

[0892] The eye and the brain are hemodynamically linked by the carotidartery and the autonomic nervous system. Pathological changes in thecarotid, brain, heart, and the sympathetic nervous system cansecondarily affect the blood flow to the eye. The eye and the brain arelow vascular resistance systems with high reactivity. The arterial flowto the brain is provided by the carotid artery. The ophthalmic arterybranches off of the carotid at a 90 degree angle and measuresapproximately 0.5 mm in diameter in comparison to the carotid whichmeasures 5 mm in diameter. Thus, most processes that affect the flow tothe brain will have a profound effect on the eye. Moreover, thepulsation of the central retinal artery may be used to determine thesystolic pressure in the ophthalmic artery, and due to its anatomicrelationship with the cerebral circulatory system, the pressure in thebrain's vessels can be estimated. Total or partial occlusion of thevascular system to the brain can be determined by evaluating the ocularblood flow. There are numerous vascular and nervous system lesions thatalter the ocular pulse amplitude and/or the intraocular pressure curveof the eye. These pathological situations may produce asymmetry ofmeasurements between the two eyes and/or a decrease of the centralretinal artery pressure, decrease of pulsatile blood flow and alter thepulse amplitude.

[0893] An obstruction in the flow in the carotid (cerebral circulation)can be evaluated by analyzing the ocular pulse amplitude and area, pulsedelay and pulse width, form of the wave and by harmonic analysis of theocular pulse.

[0894] The eye pulsation can be recorded optically according to thechange in reflection of the light beam projected to the cornea. The samesystem used to record distance traveled by the movable central pieceduring indentation can be used on the bare cornea to detect the changesin volume that occurs with each pulsation. The optical detection systemrecords the variations in distance from the surface of the cornea thatoccurs with each heart beat. These changes in the position of the corneaare induced by the volume changes in the eye. From the pulsatilecharacter of these changes, the blood flow to the eye can be calculated.

[0895] With the aforementioned technique of artificial elevation ofpressure, it is possible to measure the time necessary for the eye torecover to its baseline and this recovery time is an indicator of thepresence of glaucoma and of the coefficient of outflow facility.

[0896] The present invention may also be used to measure pressure in thevessels on the surface of the eye, in particular the pressure in theepiscleral veins. The external pressure necessary to collapse a vein isutilized in this measurement. The method involves applying a variableforce over a constant area of conjunctive overlying the episcleral veinuntil a desired end point is obtained. The pressure is applied directlyonto the vessel itself and the preferred end point is when the vesselcollapses. However, different end points may be used, such as blanchingof the vessel which occurs prior to the collapse. The pressure of theend point is determined by dividing the force applied by the area of theapplanating central piece in a similar way as is used for tonometry. Thevessel may be observed through a transparent applanating movable centralpiece using a slit-lamp biomicroscope. The embodiment for this techniquepreferably includes a modified contact device which fits on the sclera(FIG. 23). The preferred size of the tip ranges from 250 micrometers to500 micrometers. Detection of the end point can be achieved eithermanually or automatically.

[0897] According to the manual arrangement, the actuation apparatus isconfigured for direct visualization of the vessel through a transparentback window of the actuation apparatus, and the time of collapse ismanually controlled and recorded. According to an automatic arrangement,an optical detection system is configured so that, when the blood streamis no longer visible, there is a change in a reflected light beam in thesame way as described above for tonometry, and consequently, thepressure for collapse is identifiable automatically. The end pointmarking in both situations is the disappearance of the blood stream, onedetected by the operator's vision and the other detected by an opticaldetection system. Preferably, in both cases, the contact device isdesigned in a way to fit the average curvature of the sclera and themovable central piece, which can be a rigid or flexible material, isused to compress the vessel.

[0898] The present invention may also be used to provide real-timerecording of intraocular pressure. A built-in single chip microprocessorcan be made responsive to the intraocular pressure measurements overtime and can be programmed to create and display a curve relatingpressure to time. The relative position of the movable central piece canbe detected, as indicated above, using an optical detection system andthe detected position in combination with information regarding theamount of current flowing through the coil of the actuation apparatuscan be rapidly collected and analyzed by the microprocessor to createthe aforementioned curve.

[0899] It is understood that the use of a microprocessor is not limitedto the arrangement wherein curves are created. In fact, microprocessortechnology may be used to create at least the aforementioned calculationunit 10 of the present invention. A microprocessor preferably evaluatesthe signals and the force that is applied. The resulting measurementscan be recorded or stored electronically in a number of ways. Thechanges in current over time, for example, can be. recorded on astrip-chart recorder. Other methods of recording and storing the datacan be employed. Logic microprocessor control technology can also beused in order to better evaluate the data.

[0900] Still other uses of the present invention relate to evaluation ofpressure in deformable materials in industry and medicine. One suchexample is the use of the present invention to evaluate soft tissue,such as organs removed from cadavers. Cadaver dissection is afundamental method of learning and studying the human body. Thedeformability of tissues such as the brain, liver, spleen, and the like,can be measured using the present invention and the depth of indentationcan be evaluated. In this regard, the contact device of the presentinvention can be modified to fit over the curvature of an organ. Whenthe movable central piece rests upon a surface, it can be actuated toproject into the surface a distance which is inversely proportional tothe tension of the surface and rigidity of the surface to deformation.

[0901] The present invention can also be used to evaluate and quantifythe amount of cicatrization, especially in burn scar therapy. Thepresent invention can be used to evaluate the firmness of the scar incomparison to normal skin areas. The scar skin tension is compared tothe value of normal skin tension. This technique can be used to monitorthe therapy of patients with burn scars allowing a numericalquantification of the course of cicatrization. This technique can alsobe used as an early indicator for the development of hypertrophic (thickand elevated) scarring. The evaluation of the tissue pressure anddeformability in a variety of conditions such as: a) lymphoedema b)post-surgical effects, such as with breast surgery, and c) endoluminalpressures of hollow organs, is also possible with the apparatus. In theabove cases, the piston-like arrangement provided by the contact devicedoes not have to be placed in an element that is shaped like a contactlens. To the contrary, any shape and size can be used, with the bottomsurface preferably being flat and not curved like a contact lens.

[0902] Yet another use of the present invention relates to providing abandage lens which can be used for extended periods of time. Glaucomaand increased intraocular pressure are leading causes for rejection ofcorneal transplants. Many conventional tonometers in the market areunable to accurately measure intraocular pressure in patients withcorneal disease. For patients with corneal disease and who have recentlyundergone corneal transplant, a thinner and larger contact device isutilized and this contact device can be used for a longer period oftime. The device also facilitates measurement of intraocular pressure inpatients with corneal disease which require wearing of contact lenses aspart of their treatment.

[0903] The present invention may also be modified to non-invasivelymeasure infant intracranial pressure, or to provide instantaneous andcontinuous monitoring of blood pressure through an intact wall of ablood vessel. The present invention may also be used in conjunction witha digital pulse meter to provide synchronization with the cardiac cycle.Also, by providing a contact microphone, arterial pressure can bemeasured. The present invention may also be used to create a dualtonometer arrangement in one eye. A first tonometer can be defined bythe contact device of the present invention applied over the cornea, asdescribed above. The second tonometer can be defined by the previouslymentioned contact device which is modified for placement on the temporalsclera. In using the dual tonometer arrangement, it is desirable topermit looking into the eye at the fundus while the contact devices arebeing actuated. Accordingly, at least the movable central piece of thecontact device placed over the cornea is preferably transparent so thatthe fundus can be observed with a microscope.

[0904] Although the foregoing illustrated embodiments of the contactdevice generally show only one movable central piece 16 in each contactdevice 2, it is understood that more than one movable central piece 16can be provided without departing from the scope and spirit of thepresent invention. Preferably, the multiple movable central pieces 16would be concentrically arranged in the contact device 2, with at leastone of the flexible membranes 14 interconnecting the concentricallyarranged movable central pieces 16. This arrangement of multiple movablecentral pieces 16 can be combined with any of the aforementionedfeatures to achieve a desired overall combination.

[0905] Although the foregoing preferred embodiments include at least onemagnetically actuated movable central piece 16, it is understood thatthere are many other techniques for actuating the movable central piece16. Sound or ultrasound generation techniques, for example, can be usedto actuate the movable central piece. In particular, the sonic orultrasonic energy can be directed to a completely transparent version ofthe movable central piece which, in turn, moves in toward the cornea inresponse to the application of such energy.

[0906] Similarly, the movable central piece may be provided with meansfor retaining a static electrical charge. In order to actuate such amovable central piece, an actuation mechanism associated therewith wouldcreate an electric field of like polarity, thereby causing repulsion ofthe movable central piece away from the source of the electric field.

[0907] Other actuation techniques, for example, include the discharge offluid or gas toward the movable central piece, and according to a lessdesirable arrangement, physically connecting the movable central pieceto a mechanical actuation device which, for example, maybe motor drivenand may utilize a strain gauge.

[0908] Alternatively, the contact device may be eliminated in favor of amovable central piece in an actuation apparatus. According to thisarrangement, the movable central piece of the actuation apparatus may beconnected to a slidable shaft in the actuation apparatus, which shaft isactuated by a magnetic field or other actuation means. Preferably, aphysician applies the movable central piece of the actuation apparatusto the eye and presses a button which generates the magnetic field.This, in turn, actuates the shaft and the movable central piece againstthe eye. Preferably, the actuation apparatus, the shaft, and the movablecentral piece of the actuation apparatus are appropriately arranged withtransparent portions so that the inside of the patient's eye remainsvisible during actuation.

[0909] Any of the above described detection techniques, including theoptical detection technique, can be used with the alternative actuationtechniques.

[0910] Also, the movable central piece 16 may be replaced by aninflatable bladder (not shown) disposed of the substantially rigidannular member 12. When inflated, the bladder extends out of the hole inthe substantially rigid annular member 12 and toward the cornea.

[0911] Similarly, although some of the foregoing preferred embodimentsutilize an optical arrangement for determining when the predeterminedamount of applanation has been achieved, it is understood that there aremany other techniques for determining when applanation occurs. Thecontact device, for example, may include an electrical contact arrangedso as to make or break an electrical circuit when the movable centralpiece moves a distance corresponding to that which is necessary toproduce applanation. The making or breaking of the electrical circuit isthen used to signify the occurrence of applanation.

[0912] It is also understood that, after applanation has occurred, thetime which it takes for the movable central piece 16 to return to thestarting position after termination of the actuating force will beindicative of the intraocular pressure. when the intraocular pressure ishigh, the movable central piece 16 returns more quickly to the startingposition. Similarly, for lower intraocular pressures, it takes longerfor the movable central piece 16 to return to its starting position.Therefore, the present invention can be configured to also consider thereturn time of the movable central piece 16 in determining the measuredintraocular pressure.

[0913] As indicated above, the present invention maybe formed with atransparent central portion in the contact device. This transparentcentral portion advantageously permits visualization of the inside ofthe eye (for example, the optic nerve) while the intraocular pressure isartificially increased using the movable central piece. Some of theeffects of increased intraocular pressure on the optic nerve, retina,and vitreous are therefore readily observable through the presentinvention, while intraocular pressure is measured simultaneously.

[0914] With reference to FIGS. 21 and 22, although the foregoingexamples describe placement of the contact device 2 on the cornea, it isunderstood that the contact device 2 of the present invention may beconfigured with a quasi-triangular shape (defined by the substantiallyrigid annular member) to facilitate placement of the contact device 2 onthe sclera of the eye.

[0915] With reference to FIGS. 23 and 24, the contact device 2 of thepresent invention may be used to measure episcleral venous pressure.Preferably, when episcleral venous pressure is to be measured, themovable central piece 6 has a transparent centrally disposedfrustoconical projection 16P. The embodiment illustrated FIG. 24advantageously permits visualization of the subject in through at leastthe transparent central portion of the movable central piece 16.

[0916] Furthermore, as indicated above, the present invention may alsobe used to measure pressure in other parts of the body (for example,scar pressure in the context of plastic surgery) or on surfaces ofvarious objects. The contact device of the present invention, therefore,is not limited to the corneal-conforming curved shape illustrated inconnection with the exemplary embodiments, but rather may have variousother shapes including a generally flat configuration.

Alternative Embodiment Actuated by Closure of the Eye Lid

[0917] With reference to FIGS. 25-31, an alternative embodiment of thesystem will now be described. The alternative apparatus and method usesthe force and motion generated by the eye lid during blinking and/orclosure of the eyes to act as the actuation apparatus and activate atleast one transducer 400 mounted in the contact device 402 when thecontact device 402 is on the cornea. The method and device facilitatethe remote monitoring of pressure and other physiological events bytransmitting the information through the eye lid tissue, preferably viaelectromagnetic waves. The information transmitted is recovered at areceiver 404 remotely placed with respect to the contact device 402,which receiver 404 is preferably mounted in the frame 408 of a pair ofeye glasses. This alternative embodiment also facilitates utilization offorceful eye lid closure to measure outflow facility. The transducer ispreferably a microminiature pressure-sensitive transducer 400 thatalters a radio frequency signal in a manner indicative of physicalpressure exerted on the transducer 400.

[0918] Although the signal response from the transducer 400 can becommunicated by cable, it is preferably actively or passivelytransmitted in a wireless manner to the receiver 404 which is remotelylocated with respect to the contact device 402. The data represented bythe signal response of the transducer 400 can then be stored andanalyzed. Information derived from this data can also be communicated bytelephone using conventional means.

[0919] According to the alternative embodiment, the apparatus comprisesat least one pressure-sensitive transducer 400 which is preferablyactivated by eye lid closure and is mounted in the contact device 402.The contact device 402, in turn, is located on the eye. In order tocalibrate the system, the amount of motion and squeezing of the contactdevice 402 during eye lid motion/closure is evaluated and calculated. Asthe upper eyelid descends during blinking, it pushes down and squeezesthe contact device 402, thereby forcing the contact device 402 toundergo a combined sliding and squeezing motion.

[0920] Since normal individuals involuntarily blink approximately every2 to 10 seconds, this alternative embodiment of the present inventionprovides frequent actuation of the transducer 400. In fact, normalindividuals wearing a contact device 402 of this type will experience anincrease in the number of involuntary blinks, and this, in turn, tendsto provide quasi-continuous measurements. During sleep or with eyesclosed, since there is uninterrupted pressure by the eye lid, themeasurements can be taken continuously.

[0921] As indicated above, during closure of the eye, the contact device402 undergoes a combined squeezing and sliding motion caused by the eyelid during its closing phase. Initially the upper eye lid descends fromthe open position until it meets the upper edge of the contact device402, which is then pushed downward by approximately 0.5 mm to 2 mm. Thisdistance depends on the type of material used to make the structure 412of the contact device 402 and also depends on the diameter thereof.

[0922] When a rigid structure 412 is used, there is little initialoverlap between the lid and the contact device 402. When a softstructure 412 is used, there is a significant overlap even during thisinitial phase of eye lid motion. After making this initial smallexcursion the contact device 402 comes to rest, and the eye lid thenslides over the outer surface of the contact device 402 squeezing andcovering it. It is important to note that if the diameter of thestructure 412 is greater than the lid aperture or greater than thecorneal diameter, the upper lid may not strike the upper edge of thecontact device 402 at the beginning of a blink.

[0923] The movement of the contact device 402 terminates approximatelyat the corneo-scleral junction due to a slope change of about 13 degreesin the area of intersection between cornea (radius of 9 mm) and sclera(radius of 11.5 mm). At this point the contact device 402, either with arigid or soft structure 412, remains immobile and steady while the eyelid proceeds to cover it entirely.

[0924] When a rigid structure 412 is used, the contact device 402 isusually pushed down 0.5 mm to 2 mm before it comes to rest. When a softstructure 412 is used, the contact device 402 is typically pushed down0.5 mm or less before it comes to rest. The larger the diameter of thecontact device 402, the smaller the motion, and when the diameter islarge enough there may be zero vertical motion. Despite thesedifferences in motion, the squeezing effect is always present, therebyallowing accurate measurements to be taken regardless of the size of thestructure 412. Use of a thicker structure 412 or one with a flattersurface results in an increased squeezing force on the contact device402.

[0925] The eye lid margin makes a re-entrant angle of about 35 degreeswith respect to the cornea. A combination of forces, possibly caused bythe contraction of the muscle of Riolan near the rim of the eye lid andof the orbicularis muscle, are applied to the contact device 402 by theeye lid. A horizontal force (normal force component) of approximately20,000 to 25,000 dynes and a vertical force (tangential force component)of about 40 to 50 dynes is applied on the contact device 402 by theupper eye lid. In response to these forces, the contact device 402 movesboth toward the eye and tangentially with respect thereto. At the momentof maximum closure of the eye, the tangential motion and force are zeroand the normal force and motion are at a maximum.

[0926] The horizontal lid force of 20,000 to 25,000 dynes pressing thecontact device 402 against the eye generates enough motion to activatethe transducer 400 mounted in the contact device 402 and to permitmeasurements to be performed. This eye lid force and motion toward thesurface of the eye are also capable of sufficiently deforming many typesof transducers or electrodes which can be mounted in the contact device402. During blinking, the eye lids are in full contact with the contactdevice 402 and the surface of each transducer 400 is in contact with thecornea/tear film and/or inner surface of the eye lid.

[0927] The microminiature pressure-sensitive radio frequency transducer400 preferably consists of an endoradiosonde mounted in the contactdevice 402 which, in turn, is preferably placed on the cornea and isactivated by eye lid motion and/or closure. The force exerted by the eyelid on the contact device 402, as indicated above, presses it againstthe cornea.

[0928] According to a preferred alternative embodiment illustrated inFIG. 26, the endoradiosonde includes two opposed matched coils which areplaced within a small pellet. The flat walls of the pellet act asdiaphragms and are attached one to each coil such that compression ofthe diaphragm by the eye lid brings the coils closer to one another.Since the coils are very close to each other, minimal changes in theirseparation affect their resonant frequency.

[0929] A remote grid-dip oscillator 414 may be mounted at any convenientlocation near the contact device 402, for example, on a hat or cap wornby the patient. The remote grid-dip oscillator 414 is used to induceoscillations in the transducer 400. The resonant frequency of theseoscillations is indicative of intraocular pressure.

[0930] Briefly, the contact of the eye lid with the diaphragms forces apair of parallel coaxial archimedean-spiral coils in the transducer 400to move closer together. The coils constitute a high-capacitancedistributed resonant circuit having a resonant frequency that variesaccording to relative coil spacing. When the coils approach one another,there is an increase in the capacitance and mutual inductance, therebylowering the resonant frequency of the configuration. By repeatedlyscanning the frequency of an external inductively coupled oscillatingdetector of the grid-dip type, the electromagnetic energy which isabsorbed by the transducer 400 at its resonance is sensed through theintervening eye lid tissue.

[0931] Pressure information from the transducer 400 is preferablytransmitted by radio link telemetry. Telemetry is a preferred methodsince it can reduce electrical noise pickup and eliminates electricshock hazards. FM (frequency modulation) methods of transmission arepreferred since FM transmission is less noisy and requires less gain inthe modulation amplifier, thus requiring less power for a giventransmission strength. FM is also less sensitive to variations inamplitude of the transmitted signal.

[0932] Several other means and transducers can be used to acquire asignal indicative of intraocular pressure from the contact device 402.For example, active telemetry using transducers which are energized bybatteries or using cells that can be recharged in the eye by an externaloscillator, and active transmitters which can be powered from a biologicsource can also be used.

[0933] The preferred method to acquire the signal, however, involves atleast one of the aforementioned passive pressure sensitive transducers400 which contain no internal power source and operate using energysupplied from an external source to modify the frequency emitted by theexternal source. Signals indicative of intraocular ocular pressure arebased on the frequency modification and are transmitted to remoteextra-ocular radio frequency monitors. The resonant frequency of thecircuit can be remotely sensed, for example, by a grid-dip meter.

[0934] In particular, the grip-dip meter includes the aforementionedreceiver 404 in which the resonant frequency of the transducer 400 canbe measured after being detected by external induction coils 415 mountednear the eye, for example, in the eyeglass frames near the receiver orin the portion of the eyeglass frames which surround the eye. The use ofeyeglass frames is especially practical in that the distance between theexternal induction coils 415 and the radiosonde is within the typicalworking limits thereof. It is understood, however, that the externalinduction coils 415, which essentially serve as a receiving antenna forthe receiver 404 can be located any place that minimizes signalattenuation. The signal from the external induction coils 415 (orreceiving antenna) is then received by the receiver 404 foramplification and analysis.

[0935] When under water, the signal may be transmitted using modulatedsound signals because sound is less attenuated by water than are radiowaves. The sonic resonators can be made responsive to changes intemperature and voltage.

[0936] Although the foregoing description includes some preferredmethods and devices in accordance with the alternative embodiment of thepresent invention, it is understood that the invention is not limited tothese preferred devices and methods. For example, many other types ofminiature pressure sensitive radio transmitters can be used and mountedin the contact device, and any microminiature pressure sensor thatmodulates a signal from a radio transmitter and sends the modulatedsignal to a nearby radio receiver can be used.

[0937] Other devices such as strain gauges, preferably piezoelectricpressure transducers, can also be used on the cornea and are preferablyactivated by eye lid closure and blinking. Any displacement transducercontained in a distensible case also can be mounted in the contactdevice. In fact, many types of pressure transducers can be mounted inand used by the contact device. Naturally, virtually any transducer thatcan translate the mechanical deformation into electric signals isusable.

[0938] Since the eye changes its temperature in response to changes inpressure, a pressure-sensitive transducer which does not require motionof the parts can also be used, such as a thermistor. Alternatively, thedielectric constant of the eye, which also changes in response topressure changes, can be evaluated to determine intraocular pressure. Inthis case, a pressure-sensitive capacitor can be used. Piezoelectric andpiezo-resistive transducers, silicon strain gauges, semiconductordevices and the like can also be mounted and activated by blinkingand/or closure of the eyes.

[0939] In addition to providing a novel method for performing singlemeasurements, continuous measurements, and self-measurement ofintraocular pressure during blinking or with the eyes closed, theapparatus can also be used to measure outflow facility and otherphysiological parameters. The inventive method and device offer a uniqueapproach to measuring outflow facility in a physiological manner andundisturbed by the placement of an external weight on the eye.

[0940] In order to determine outflow facility in this fashion, it isnecessary for the eye lid to create the excess force necessary tosqueeze fluid out of the eye. Because the present invention permitsmeasurement of pressure with the patient's eyes closed, the eye lids canremain closed throughout the procedure and measurements can be takenconcomitantly. In particular, this is accomplished by forcefullysqueezing the eye lids shut. Pressures of about 60 mm Hg will occur,which is enough to squeeze fluid out of the eye and thus evaluateoutflow facility. The intraocular pressure will decrease over time andthe decay in pressure with respect to time correlates to the outflowfacility. In normal individuals, the intraocular fluid is forced out ofthe eye with the forceful closure of the eye lid and the pressure willdecrease accordingly; however, in patients with glaucoma, the outflow iscompromised and the eye pressure therefore does not decrease at the samerate in response to the forceful closure of the eye lids. The presentsystem allows real time and continuous measurement of eye pressure and,since the signal can be transmitted through the eye lid to an externalreceiver, the eyes can remain closed throughout the procedure.

[0941] Telemetry systems for measuring pressure, electrical changes,dimensions, acceleration, flow, temperature, bioelectric activity,chemical reactions, and other important physiological parameters andpower switches to externally control the system can be used in theapparatus of the invention. The use of integrated circuits and technicaladvances occurring in transducer, power source, and signal processingtechnology allow for extreme miniaturization of the components which, inturn, permits several sensors to be mounted in one contact device, asillustrated for example in FIG. 28.

[0942] Modern resolutions of integrated circuits are in the order of afew microns and facilitate the creation of very high density circuitarrangements. Preferably, the modem techniques of manufacturingintegrated circuits are exploited in order to make electronic componentssmall enough for placement on the eyeglass frame 408. The receiver 404,for example, may be connected to various miniature electronic components418, 419, 420, as schematically illustrated in FIG. 31, capable ofprocessing, storing, and even displaying the information derived fromthe transducer 400.

[0943] Radio frequency and ultrasonic micro-circuits are available andcan be mounted in the contact device for use thereby. A number ofdifferent ultrasonic and pressure transducers are also available and canbe used and mounted in the contact device. It is understood that furthertechnological advances will occur which will permit further applicationsof the apparatus of the invention.

[0944] The system may further comprise a contact device for placement onthe cornea and having a transducer capable of detecting chemical changesin the tear film. The system may further include a contact device forplacement on the cornea and having a microminiature gas-sensitive radiofrequency transducer (e.g., oxygen-sensitive). A contact device having amicrominiature blood velocity-sensitive radio frequency transducer mayalso be used for mounting on the conjunctiva and is preferably activatedby eye lid motion and/or closure of the eye lid.

[0945] The system also may comprise a contact device in which a radiofrequency transducer capable or measuring the negative resistance ofnerve fibers is mounted in the contact device which, in turn, is placedon the cornea and is preferably activated by eye lid motion and/orclosure of the eye lid. By measuring the electrical resistance, theeffects of microorganisms, drugs, poisons and anesthetics can beevaluated.

[0946] The system of the present invention may also include a contactdevice in which a microminiature radiation-sensitive radio frequencytransducer is mounted in the contact device which, in turn, is placed onthe cornea and is preferably activated by eye lid motion and/or closureof the eye lid.

[0947] In any of the foregoing embodiments having a transducer mountedin the contact device, a grid-dip meter can be used to measure thefrequency characteristics of the tuned circuit defined by thetransducer.

[0948] Besides using passive telemetry techniques as illustrated by theuse of the above transducers, active telemetry with active transmittersand a microminiature battery mounted in the contact device can also beused.

[0949] The contact device preferably includes a rigid or flexibletransparent structure 412 in which at least one of the transducers 400is mounted in hole(s) formed in the transparent structure 412.Preferably, the transducers 400 is/are positioned so as to allow thepassage of light through the visual axis. The structure 412 preferablyincludes an inner concave surface shaped to match an outer surface ofthe cornea.

[0950] As illustrated in FIG. 29, a larger transducer 400 can becentrally arranged in the contact device 402, with a transparent portion416 therein preserving the visual axis of the contact device 402.

[0951] The structure 412 preferably has a maximum thickness at thecenter and a progressively decreasing thickness toward a periphery ofthe structure 412. The transducers is/are preferably secured to thestructure 412 so that the anterior side of each transducer 400 is incontact with the inner surface of the eye lid during blinking and sothat the posterior side of each transducer 400 is in contact with thecornea, thus allowing eye lid motion to squeeze the contact device 402and its associated transducers 400 against the cornea.

[0952] Preferably, each transducer 400 is fixed to the structure 412 insuch a way that only the diaphragms of the transducers experience motionin response to pressure changes. The transducers 400 may also have anysuitable thickness, including matching or going beyond the surface ofthe structure 412.

[0953] The transducers 400 may also be positioned so as to bear againstonly the cornea or alternatively only against the inner surface of theeye lid. The transducers 400 may also be positioned in a protruding waytoward the cornea in such a way that the posterior part flattens aportion of the cornea upon eye lid closure. Similarly, the transducers400 may also be positioned in a protruding way toward the inner surfaceof the eye lid so that the anterior part of the transducer 400 ispressed by the eye lid, with the posterior part being covered by aflexible membrane allowing interaction with the cornea upon eye lidclosure.

[0954] A flexible membrane of the type used in flexible or hydrogellenses may encase the contact device 402 for comfort as long as it doesnot interfere with signal acquisition and transmission. Although thetransducers 400 can be positioned in a manner to counterbalance eachother, as illustrated in FIG. 28, it is understood that a counter weightcan be used to maintain proper balance.

[0955]FIG. 32 illustrates the contact device 500 placed on the surfaceof the eye with mounted sensor 502, transmitter 504, and power source506 which are connected by fine wire 508 (shown only partially extendingfrom sensor 502 and from transmitter 504), encased in the contactdevice. The contact device shown measures approximately 24 mm in itslargest diameter with its corneal portion 510 measuring approximately 11mm in diameter with the remaining 13 mm subdivided between 8 mm of aportion 512 under the upper eyelid 513 and 5 mm of a portion 514 underthe lower eyelid 515. The contact device in FIG. 32 hasmicroprotuberances 516 in its surface which increases friction andadhesion to the conjunctiva allowing diffusion of tissue fluid from theblood vessels into the sensor selective membrane surface 518. The tissuefluid goes through membranes in the sensor and reaches an electrode 520with generation of current proportional to the amount of analyte foundin the tear fluid 522 moving in the direction of arrows 524. Atransmitter 504 transmitting a modulated signal 526 to a receiver 528with the signal 526 being amplified and filtered in amplifier and filter529, decoded in demultiplexes 530, processed in CPU 532, displayed atmonitor 534, and stored in memory 536.

[0956] The contact device 540 shown in FIG. 33A includes two sensors,one sensor 542 for detection of glucose located in the main body 544 ofthe contact device and a cholesterol sensor 546 located on a myoflange548 of the contact device 540. Forming part of the contact device is aheating electrode 550 and a power source 552 next to the cholesterolsensor 546 with the heating electrode 550 increasing the localtemperature with subsequent transudation of fluid in the direction ofarrows 553 toward the cholesterol sensor 546.

[0957] In one embodiment the cholesterol sensor shown in FIG. 33Cincludes an outer selectively permeable membrane 554, and mid-membranes556, 558 with immobilized cholesterol esterase and cholesterol oxidaseenzymes and an inner membrane 560 permeable to hydrogen peroxide. Theexternal membrane 554 surface has an area preferably no greater than 300square micrometers and an overall thickness of the multiple membranelayers is in the order of 30-40 micrometers. Covered by the innermembrane are a platinum electrode 562 and two silver electrodes 564measuring 0.4 mm (platinum wire) and 0.15 mm (silver wire). Fine wires566, 568 connect the cholesterol sensor 546 to the power source 552 andtransmitter 570. The glucose sensor 542 includes a surrounding irregularexternal surface 572 to increase friction with the sensor connected byfine wires 574, 576 to the power source 578 and transmitter 570. Thepower source 578 is connected to the sensor in order to power the sensor542 for operation.

[0958] The transmitter includes integrated circuits for receiving andtransmitting the data with the transmitters being of ultra denseintegrated hybrid circuits measuring approximately 500 microns in itslargest dimension. The corneal tissue fluid diffuses in the direction ofarrows 580 toward the glucose sensor 542 and reaches an outer membrane582 permeable to glucose and oxygen followed by an immobilized glucoseoxidase membrane 584 and an inner membrane 586 permeable to hydrogenperoxide. The tissue fluid then reaches the one platinum 588 and twosilver 590 electrodes generating a current proportional to theconcentration of glucose. The dimensions of the glucose sensor aresimilar to the dimensions of the cholesterol sensor.

[0959]FIG. 34 illustrates by, a block diagram, examples of signalsobtained for measuring various biological variables such as glucose 600,cholesterol 602 and oxygen 604 in the manner as exemplified in FIGS.33A-33C. A glucose signal 606, a cholesterol signal 608 and an oxygensignal 610 are generated by transducers or sensors as shown in FIGS. 33Band 33C. The signals are transmitted to a multiplexer 612 whichtransmits the signals as a coded signal by wire 614 to a transmitter616. A coded and modulated signal is transmitted, as represented by line618, by radio, light, sound, wire telephone or the like with noisesuppression to a receiver 620. The signal is then amplified and filteredat amplifier and filter 622. The signal passes through a demultiplexer624 and the separated signals are amplified at 626, 628, 630,respectively and transmitted and displayed at display 632 of a CPU andrecorded for transmission by modem 634 to an intensive care unit, forexample.

[0960] FIGS. 35A-35C illustrate an intelligent contact lens beingactivated by closure of the eyelids with subsequent increased diffusionof blood components to the sensor. During movement of the eye lids fromthe position shown in FIG. 35C to the position shown in FIG. 35A byblinking and/or closure of the eye, a combination of forces are appliedto the contact device 636 by the eyelid with a horizontal force (normalforce component) of approximately 25,000 dynes which causes an intimateinteraction between the contact device and the surface of the eye with adisruption of the lipid layer of the tear film allowing directinteraction of the outer with the palpebral conjunctiva as well as adirect interaction of the inner surface of the contact device with theaqueous layer of the tear film and the epithelial surface of the corneaand bulbar conjunctiva. Blinking promotes a pump system which extractsfluid from the supero-temporal corner of the eye and delivery of fluidto the puncta in the infero-medial corner of the eye creating acontinuous flow which bathes the contact device. During blinking, theclose interaction with the palpebral conjunctiva, bulbar conjunctiva,and cornea, the slightly rugged surface of the contact device createsmicrodisruption of the blood barrier and of the epithelial surface withtransudation and increased flow of tissue fluid toward the surface ofthe contact device. The tear fluid then diffuses through the selectivelypermeable membranes located on the surface of the contact device 636 andsubsequently reaching the electrodes of the sensor 638 mounted in thecontact device. In the preferred embodiment for glucose measurement,glucose and oxygen flow from the capillary vessels 640 toward aselectively permeable outer membrane and subsequently reach amid-membrane with immobilized glucose oxidase enzyme. At this layer ofimmobilized glucose oxidase enzyme, a enzymatic oxidation of glucose inthe presence of the enzyme oxidase and oxygen takes place with theformation of hydrogen peroxide and gluconic acid. The hydrogen peroxidethen diffuses through an inner membrane and reaches the surface of aplatinum electrode and it is oxidized on the surface of the workingelectrode creating a measurable electrical current. The intensity of thecurrent generated is proportional to the concentration of hydrogenperoxide which is proportional to the concentration of glucose. Theelectrical current is subsequently converted to a frequency audio signalby a transmitter mounted in the contact device with signals beingtransmitted to a remote receiver using preferably electromagnetic energyfor subsequent amplification, decoding, processing, analysis, anddisplay.

[0961] In FIGS. 36A through 36J, various shapes of contact devices areshown for use in different situations. In FIG. 36A, a contact device 642is shown of an elliptical, banana or half moon shape for placement underthe upper or lower eye lid. FIGS. 36B and 36C show a contact device 644having, in side view a wide base portion 646 as compared to an upperportion 648. FIG. 36D shows a contact device 650 having a truncated lensportion 652.

[0962] In FIGS. 36E and 36F, the contact device 654 is shown in sideview in FIG. 36E and includes a widened base portion 656 which as shownin FIG. 36F is of a semi-truncated configuration.

[0963]FIG. 36G shows a contact device 658, having a corneal portion 650and a scleral portion 652. In FIG. 36H, an oversized contact device 664,includes a corneal portion 666 and a scleral portion 668.

[0964] A more circular shaped contact device 670 is shown in FIG. 36Ihaving a corneal-scleral lens 672.

[0965] The contact device 674 shown in FIG. 36J is similar to the onesshown in FIGS. 32, 33A, 35A and 35C. The contact device includes a mainbody portion 676 with upper myoflange or minus carrier 678 and lowermyoflange or minus carrier 680.

[0966] In FIG. 37A, an upper contact device 682 is placed under an uppereye lid 684. Similarly, a lower contact device 686 is placed underneatha lower eye lid 688. Upper contact device 682 includes an oxygensensor/transmitter 690 and a glucose transmitter 692. Similarly, thelower contact device includes a temperature sensor transmitter 694 and apH sensor/transmitter 696.

[0967] Each of these four sensors outputs a signal to respectivereceivers 698, 700, 702 and 704, for subsequent display in CPU displays706, 708, 710, 712, respectively. The CPUs display an indication of asensed oxygen output 714, temperature output 716, pH output 718 andglucose output 720.

[0968] In FIG. 37B, a single contact device 722, in an hour glass shape,includes an upper sodium sensor/transmitter 724 and a lower potassiumsensor/transmitter 726. The two sensors send respective signals toreceivers 728 and 730 for display in CPUs 732, 734 for providing asodium output indicator 736 and a potassium output indicator 738.

[0969] In FIG. 38A, a contact device 740 is shown which may be formed ofan annular band 742 so as to have a central opening with the openingoverlying a corneal portion or if the contact device includes a cornealportion, the corneal portion lays on the surface of the cornea.

[0970] Limited to annular band 742 is a sensor 744 positioned on thescleral portion of the contact device so as to be positioned under aneye lid. The sensor is connected by wires 746 a, 746 b to transmitter748 which is in communication with the power source 750 by wires 752 a,752 b. The intelligent contact lens device 740 is shown in section inFIG. 38B with the power source 750 and sensor 744 located on oppositeends of the contact device on the scleral portion of the contact device.

[0971]FIG. 39A schematically illustrates the flow of tear fluid asillustrated by arrows 754 from the right lacrimal gland 756 across theeye to the lacrimal punctum 758 a and 758. Taking advantage of the flowof tear fluid, in FIG. 39B, a contact device 760 is positioned in thelower cul-de-sac 762 beneath the lower eye lid 764 so that a pluralityof sensors 764 a, 764 b and 764 c in wire communication with a powersource 766 and transducer 768 can be connected by a wire 770 to anexternal device. The flow of tear fluid from the left lacrimal gland 762to the lacrimal punctum 764 a and 764 b is taken advantage of to producea reading indicative of the properties to be detected by the sensors.

[0972] In FIG. 40A, a contact device 772 is positioned in the cul-de-sac774 of the lower eye lid 776. The contact device includes a needle-typeglucose sensor 778 in communication with a transmitter 780 and a powersource 782. A signal 782 is transmitted to a receiver, demultiplexer andamplifier 784 for transmission to a CPU and modem 786 and subsequenttransmission over a public communication network 788 for receipt andappropriate action at an interface 790 of a hospital network.

[0973] In FIG. 40B, a similar arrangement to that shown in FIG. 40A isused except the glucose sensor 792 is a needle type sensor with a curvedshape so as to be placed directly against the eye lid. The sensor 792 issilicone coated or encased by coating with silicone for comfortable wearunder the eye lid 794. Wires 796 a and 796 b extend from under the eyelid and are connected to an external device. The sensor 792 is placed indirect contact with the conjunctiva with signals and power sourceconnected by wires to external devices.

[0974]FIG. 41 shows an oversized contact device 798 including sensors800 a, 800 b, 800 c and the scleral portion of the contact device to bepositioned under the upper eye lid. In addition, sensors 802 a, 802 b,802 c are to be positioned under the lower eye lid in contact with thebulbar and/or palpebral conjunctiva. In addition, sensors 804 a-d arelocated in the corneal portion in contact with the tear film over thecornea.

[0975]FIG. 42A shows a contact device 806 having a sensor 808 and atransmitter 810 in position, at rest, with the eye lids open. However,in FIG. 42B, when the eye lids move towards a closed position, and theindividual is approaching a state of sleep, the Bell phenomenon willmove the eye and therefore the contact device upward in the direction ofarrows 812. The pressure produced from the eye lid as the contact devicemoves up, will produce a signal 814 from the sensor 808 which istransmitted to a receive 816. The signal passes through an amplifier andfilter 818 to a demultiplexer. 820 for activation of an alarm circuit822 and display of data at 824. The alarm should be sufficient to wake adozing driver or operator of other machinery to alert the user of signsof somnolence.

[0976] In FIG. 43, a heat stimulation transmission device 825 forexternal placement on the surface of the eye is shown for placement onthe scleral and corneal portions of the eye. The device 825 includes aplurality of sensors 826 spaced across the device 825. With reference toFIG. 44, the device 825 includes heating elements 828 a-c, a thermistor830, an oxygen sensor 832, and a power source 834. Signals generated bythe sensors are transmitted by transmitter 836 to hardware 838 whichprovides an output representative of a condition detected by thesensors.

[0977] In FIG. 46, an annular band 840 includes a plurality of devices842 a-e. The annular band shaped heat stimulation transmission device840 can be used externally or internally by surgical implication in anypart of the body. Another surgically implantable device 844 is shown inFIG. 46. In this example, the heat stimulation transmission device 844is implanted between eye muscles 846, 848. Another example of asurgically implantable heat stimulation transmission device 850 is shownin FIG. 47, having four heating elements 852, a temperature sensor 854and an oxygen sensor 856, with a power source 858 and a transmitter 860for transmitting signal 852.

[0978]FIGS. 48, 49 and 51 through 53 illustrate the use of anoverheating transmission device, as shown in FIG. 50, for thedestruction of tumor cells after the implantation of the overheatingtransmission device by surgery. As shown in FIG. 50, the overheatingtransmission device 864 includes a plurality of heating elements 866 a,866 b, 866 c, a temperature sensor 868, a power source 870 which isinductively activated and a transmitter 872 for transmitting a signal874. By activation of the device 864, an increase in temperature resultsin the immediately adjacent area. This can cause the distruction oftumor cells from a remote location.

[0979] In FIG. 48, the device 864 is located adjacent to a brain tumor876. In FIG. 49, the device 864 is located adjacent to a kidney tumor878.

[0980] In FIG. 51, the device 864 is located adjacent to an intraoculartumor 880. In FIG. 52, a plurality of devices 864 are located adjacentto a lung tumor 882. In FIG. 53, a device 864 is located externally onthe breast, adjacent to a breast tumor 884.

[0981] In FIGS. 54A and 54B, a contact device 886 is located on the eye888. The contact device is used to detect glucose in the aqueous humorby emitting light from light emitting optical fiber 890, which issensitive to glucose, as compared to a reference optical fiber lightsource 892, which is not sensitive to glucose. Two photo detectors 894a, 894 b measure the amount of light passing from the reference opticalfiber 892 and the emitting optical fiber 890 sensitive to glucose andtransmit the received signals by wires 896 a, 896 b for analysis.

[0982] In FIG. 54C, a glucose detecting contact device 900 is usedhaving a power source 902, an emitting light source 904 sensitive toglucose and a reference light source 906, non-sensitive to glucose. Twophoto detectors 908 a and 908 b, provide a signal to a transmitter 910for transmission of a signal 912 to a remote location for analysis andstorage.

[0983] In FIG. 55A, a contact device 914 is positioned on an eye 916 fordetection of heart pulsations or heart sounds as transmitted to eye 916by the heart 918 as a normal bodily function. A transmitter provides asignal 920 indicative of the results of the heart pulsations or heartsound. A remote alarm device 922 may be worn by the individual. Thedetails of the alarm device are shown in FIG. 55B where the receiver 924receives the transmitted signal 920 and conveys the signal to a displaydevice 926 as well as to an alarm circuit 928 for activation of an alarmif predetermined parameters are exceeded.

[0984] In FIG. 56, a contact device 930 is shown. The contact deviceincludes an ultra sound sensor 932, a power source 934 and a transmitter936 for conveying a signal 938. The ultra sound sensor 932 is placed ona blood vessel 940 for measurement of blood flow and blood velocity. Theresult of this analysis is transmitted by signal 938 to a remotereceiver for analysis and storage.

[0985] In FIG. 57, an oversized contact device 940 includes a sensor942, a power source 944 and a transmitter 946 for transmitting a signal948. The sensor 942 is positioned on the superior rectus muscle formeasurement of eye muscle potential. The measured potential istransmitted by signal 948 to a remote receiver for analysis and storage.

[0986] In FIG. 58A, a contact device 950 includes a light source 952, apower source 954, multioptical filter system 956 and a transmitter 958for transmission of a signal 960. The light source 952 emits a beam oflight to the optic nerve head 962. The beam of light is reflected on tothe multioptical filter system 956 for determination of the angle ofreflection.

[0987] As shown in FIG. 58B, since the distance X of separation betweenthe multioptical filter system and the head of the optic nerve 962remains constant as does the separation distance Y between the lightsource 952 and the multoptical filter system 956, a change in the pointP which is representative of the head of the optic nerve will cause aconsequent change in the angle of reflection so that the reflected lightwill reach a different point on the multioptical filter system 956. Thechange of the reflection point on multioptical filter system 956 willcreate a corresponding voltage change based on the reflection angle. Thevoltage signal is transmitted as an audio frequency signal 960 to aremote location for analysis and storage.

[0988] In FIGS. 59A through 59C, a neuro stimulation transmission device964 is shown. In FIG. 59A, the device 964 is surgically implanted in thebrain 966. The device 964 includes microphotodiodes or electrodes 968and a power source/transmitter 970. The device is implanted adjacent tothe occipital cortex 972.

[0989] In FIG. 59B, the device 964 is surgically implanted in the eye974 on a band 976 including microphotodiodes 978 a, 978 b with a powersource 980 and a transmitter 982.

[0990] In FIG. 59C, the device 964 is externally placed on the eye 974using an oversized contact device 984 as a corneal scleral lens. Thedevice includes an electrode 986 producing a microcurrent, amicrophotodiode or electrode 988, a power source 990 and a transmitter992 for transmission of a signal to a remote location for analysis andstorage.

[0991] In FIG. 60, a contact device 1000 includes a power source 1002and a fixed frequency transmitter 1004. The transmitter 1004 emits afrequency which is received by an orbiting satellite 1006. Upondetection of the frequency of the signal transmitted by the transmitter1004, the satellite can transmit a signal for remote receptionindicative of the location of the transmitter 1004 and accordingly theexact location of the individual wearing the contact device 1000. Thiswould be useful in military operations to constantly monitor thelocation of all personal.

[0992] In FIG. 61, a contact device 1008 is located below the lower eyelid 1010. The contact device includes a pressure sensor, an integratedcircuit 1012, connected to an LED drive 1014 and an LED 1016. A powersource 1018 is associated with the device located in the contact device1008.

[0993] By closure of the eye 1020 by the eye lids, the pressure sensor1012 would be activated to energize the LED drive and therefore the LEDfor transmission of a signal 1020 to a remote photodiode or opticalreceiver 1022 located on a receptor system. The photodiode or opticalreceiver 1022, upon receipt of the signal 1020, can transmit a signal1024 for turning on or off a circuit. This application has may uses forthose individuals limited in their body movement to only their eyes.

[0994] In FIG. 62, a contact device 1026 includes compartments 1028,1030 which include a chemical or drug which can be dispensed at thelocation of the contact device 1026. The sensor 1032 provides an signalindicative of a specific condition or parameter to be measured. Basedupon the results of the analysis of this signal, when warranted, bylogic circuit 1034, a heater device 1036 can be activated to melt athread or other closure member 1038 sealing the compartments 1028, 1030so as to allow release of the chemical or drug contained in thecompartments 1028, 1030. The system is powered by power source 1040based upon the biological variable signal generated as a result ofmeasurement by sensor 1032.

[0995] According to the system shown in FIG. 63, a glucose sensor 1042,positioned on the eye 1044, can generate a glucose level signal 1046 toa receiver 1048 associated with an insulin pump 1050 for release ofinsulin into the blood stream 1052. The associated increase in insulinwill again be measured on the eye 1044 by the sensor 1042 so as tocontrol the amount of insulin released by the insulin pump 1050. Aconstant monitoring system is thereby established

[0996] In reference to FIGS. 64A through 64D there is shown the stepsfor the experimental in-vitro testing according to the biologicalprinciples of the invention. The biological principles of the currentinvention include the presence of superficially located fenestratedblood vessels in the conjunctiva allowing tissue fluid to freely flowfrom the vessels of the eye for analysis. FIGS. 64A-64D shows theschematic illustration of the testing of an eye to confirm the locationof fenestated vessels. A side view of the eye ball in FIG. 64A shows theconjunctiva 1110 with its vessels 1112 covering both the eye ball 1114and the eye lid (not shown). A main conjunctival vessel 1116 in thelimbal area shown in FIG. 64B is then cannulated and fluorescein dye1118 injected through syringe 1119 into the vessel 1116. The dye startsto leak from the fenestrated vessels into the conjunctival space 1120and surface of the eye 1122 in mid-phase in FIG. 64C. In the late phase(FIG. 64D) there is a massive leakage 1124 of fluid (fluorescein dye)completely covering the surface of the eye due to the presence ofsuperficially located fenestrated vessels.

[0997] Another experiment consisted of attaching a glucose oxidase stripto a variety of contact lens materials which were subsequently placed inthe eye lid pocket. Blood samples were acquired from non-diabeticsubjects using whole blood from the tip of the finger. The glucoseoxidase enzyme detects the oxidable species present in the eye, in thisexample, the amount of glucose. The enzymes are coupled to a chromogenwhich created a color change based on the amount of the analyte(glucose). A combination of the forces caused by the physiologicmuscular activity of the orbicularis muscle and muscle of Riolam in theeye lid generating a normal force component of 25,000 dynes acts on thecontact device which promotes a fluid flux of analyte toward the stripwith the subsequent development of color changes according to the amountof glucose. Fasting plasma concentration of glucose as identified by thecontact lens system of the current invention was 15% higher than wholeblood which corresponds to the physiologic difference between wholeblood glucose and plasma glucose.

[0998] In reference to FIGS. 65A-65F there are shown a series ofpictures related to in-vivo testing in humans related to the biologicalprinciples of the invention. FIGS. 65A through 65F show an angiogram ofconjunctival blood vessels present on the surface of the eye in a normalhealthy living human subject. The fluorescein dye is injected into thevein of the subject and serial photographs with special illumination andfilters are taken from the surface of the eye. The fluorescein angiogramallows evaluation of the anatomic structure and integrity of bloodvessels as well as their physiologic behavior. Vessels which do not leakkeep the fluorescein dye (seen as white) inside the vessel and appear asstraight lines. Vessels in which there is leakage appear as white linessurrounded by white areas. The white areas represent the fluorescein(white) which left the vessels and is spreading around said bloodvessels. Since there is continuous leakage as the dye reaches theconjunctiva, as time progresses the whole area turns white due to thewidespread and continuous leakage.

[0999]FIG. 65A shows a special photograph of the conjunctiva before dyeis injected and the area appears as black. About 15 seconds after thedye is injected into a vein of a patient, the dye appears in theconjunctiva and starts to fill the conjunctival blood vessels (FIG.65B). The initial filling of few conjunctival vessels is followed byfilling of other vessels after 22 seconds from injection into the vein(FIG. 65C) with progressive leakage of the dye from the conjunctivalvessels forming the fluffy white images around the vessels as filling ofvessels progresses. After about 30 seconds from the time of injectionmost of the conjunctival vessels begin to leak due to fenestration whichis observed as large white spots. In the late phase, leakage fromconjunctival vessels has increased markedly and reaches the surfaceengulfing the whole conjunctival area as shown in FIG. 65D. Note theintense hyper-fluorescence (white areas) due to leakage that is presentin the conjunctiva.

[1000] As with FIG. 68 which shows junction of conjunctiva and skin,FIG. 65E shows the junction of conjunctiva and cornea. According to thebiological principles of the invention one can easily see the differencebetween vessels with holes (conjunctiva) and vessels without holes(limbal area which is the transition zone between conjunctiva andcornea).

[1001]FIG. 65E (photo A) shows an enlarged view of late phase withleakage by conjunctival vessels pointed by the large arrow heads withthe conjunctival vessels surrounded by fluffy white areas (=leakage).Contrary to that, when one leaves the conjunctiva the vessels arenon-fenestrated (=no holes) and thus the vessels are observed asstraight white lines without surrounding fluffy white areas. Note thatno leakage is seen from vessels next to the cornea (triple arrows) whichare seen as straight white lines without surrounding white infiltrateswhich means no leakage. Only the conjunctival vessels have fenestration(pores) and leakage of plasma to the surface allowing any analytes andcells present in the eye to be measured.

[1002]FIG. 65F (photo B) is an enlarged view showing the complete lackof leakage by the non-conjunctival blood vessels in the transitionbetween cornea and conjunctiva which are seen as white straight lines.

[1003] Note that these conjunctival vessels leaking fluid (see FIGS.65C-65E, for example) are part the lining of the eye lid pockets inwhich to insert the ICL according to the principles of the presentinvention. It takes about 10 seconds from the time the dye is injectedin the vein until it reaches the eye. The time correlates with thepumping action of the heart. As long as the heart is pumping blood, theconjunctival vessels will continue to leak allowing the continuousnon-invasive measurement of blood elements according to the principlesof the invention.

[1004] Please note that the conjunctiva is the only superficial organwith such fenestrated blood vessels. There are areas inside the bodysuch as liver and kidney with fenestrated vessels but for obviousreasons such organs are not accessible for direct non-invasivecollection and analysis of plasma. As previously described theconjunctiva posses all of the characteristics needed for non-invasiveand broad diagnostics including fluid and cells for analysis.

[1005]FIGS. 66A through 66C are schematic illustrations of an angiogram.FIG. 66A shows initial filling of conjunctival vessels 1150 withfluorescein dye. The lower eye lid 1152 with eye lashes 1153 was pulleddown to expose the conjunctival vessels 1150 present in the eye lidpocket 1154. FIGS. 66A through 66C also show the cornea 1156 and pupil1157′ of the eye located above the conjunctival area 1154. FIG. 66Bshows mid-phase filling of conjunctival vessels with leakage representedby large arrow heads 1158. The same figure also shows the lack ofleakage in the vessels next to the cornea represented by triple arrows1160 indicating the presence of fenestrated vessels only in theconjunctival area 1154. FIG. 66C shows a late phase of the angiogram ofthe conjunctival vessels with almost complete filling of theconjunctival space and surface 1162 of the eye in the eyelid pocket1154. Note that the limbal vessels (not fenestrated, no holes) remain asstraight, white lines without leakage.

[1006]FIGS. 67A and 67B show a schematic representation of the bloodvessels found in the conjunctiva with fenestrations (holes) in FIG. 67Bcompared to continuous blood vessels (no holes) in FIG. 67A. Thefenestrated vessels in the conjunctiva have a discontinuous flatmembrane as thin as 40 angstroms in thickness and perforated by poresmeasuring about 600 to 700 angstroms. This structural arrangement is ofprime importance in the permeability functions of the vessel, allowingplasma to freely leave the vessel, and thus any substance and/or cellpresent in the plasma can be evaluated according to the principles ofthe current invention. Contrary to FIG. 67B, FIG. 67A shows continuouswalled vessels with complete lining of endothelial cells and continuousbasement membrane which does not allow leakage or external flow of bloodcomponents. Those non-fenestrated vessels are commonly found in thesubcutaneous layer deep under the skin, muscle tissue and connectivetissues.

[1007] Besides demonstrating that functionally and physiologically theconjunctiva and the eye provides the ideal characteristics fordiagnostics with superficial vessels that leak fluid, the inventor alsodemonstrated from a morphologic standpoint that the conjunctival areaand the eye have the ideal anatomic characteristics for the measurementsaccording to the principles of the present invention. Thus, FIG. 68Ashows a microphotograph depicting the microscopic structure of thejunction (arrow) 1163 between conjunctiva and skin present in the eyelid of a normal adult individual.

[1008] This junction 1163 which lies next to the eye lash line is calledthe lid margin mucosal-cutaneous junction and provides a greatillustration for comparison between the skin and conjunctiva of thecurrent invention. The skin has previously been used for acquiring bloodinvasively as with needles and lasers or minimally invasively as withelectroporation, electroosmosis, and the like. However besides nothaving the superficial fenestrated blood vessels, one can clearly see bythis photograph that the skin is not suitable for such evaluations. Thearrow points to the junction 1163 of skin and conjunctiva. To the leftof the junction arrow 1163 the epithelium of the skin 1164 is seen asthis dark layer of varying thickness in a wave-like shape. Theepithelium of the skin consists of densely organized multiplenon-homogeneous cell layers overlying a thick and continuous tight basecell layer. The dark band is very thick and associated with largeappendages such as a duct of a sebaceous gland 1164 a. The tissue 1164 bunder the black thick superficial band is also thick (dark gray color)because it is composed of dense tissue. The blood vessels 1167 arelocated deep in the subcutaneous area.

[1009] Compare now to the conjunctiva on the right of the junction arrow1163. The epithelium 1165 is so thin that one can barely identify adarker band superficially located in the photomicrograph. Theconjunctiva is transparent and can be illustrated as a very thincellophane-like material with blood vessels 1166. The epithelium of theconjunctiva 1165 besides being thin, as shown in FIGS. 68A and 68C isalso quite homogeneous in thickness and becomes even thinner as onemoves away from the skin (far right). The epithelium of the conjunctiva1165 consists of a few loosely organized cell layers overlying a thin,discontinuous basement membrane with few hemidesmossomes and very wideintercellular spaces. The tissue underneath the thin epithelium of theconjunctival 1165 is whitish (much lighter than the tissue under thethick dark skin epithelium). The reason for the whitish appearance isthat the conjunctiva has a very loose substantia propria and looseconnective tissue allowing easy permeation of fluid through thoselayers. The skin which is thick and dense does not provide the same easypassage of fluid. The conjunctiva has a voluminous blood supply and thevessels 1166 in the conjunctiva are right underneath the surfaceallowing immediate reach and permeation to the surface with the adjunctpump function of the eye lid tone. FIG. 68B shows the junction (arrow)1163 in accordance with FIG. 68A. The illustration includes theepithelium 1164, and blood vessels 1167 of the skin of the eye lid andblood vessels 1166 and epithelium 1165 (shown as a single top line) ofthe conjunctiva. FIG. 68B also includes muscles and ligaments inproximity to the conjunctiva and eye lid pocket such as the inferiortarsal muscle 1168, the lower lid retractors 1169, the inferiorsuspensory ligament of Lockwood 1170, and the inferior rectus muscle1171. Although, the eye lid has the thinnest skin in the body, the bloodvessels are still incredibly deeply located when compared to theconjunctival vessels. These muscles 1168, 1169, 1170, 1171 which are inproximity to the conjunctiva can be used as a electromechanical sourceof energy for the Implantable ICLs.

[1010]FIGS. 69A and 69B show the surprising large conjunctival area fordiagnostics in accordance with the present invention. There are twolarge pockets, one superior 1180 and one inferiorly 1182. These eye lidspockets are lined by the vascularized conjunctiva. The pocket formed bythe upper eye lid measures in height about 10 to 12 mm in a half moonshape by 40 mm in length. The lower eye lid pocket measures about 8 to10 mm in height by 40 mm in length and can easily accommodate an ICL1184 according to the principles of the invention. FIG. 69A also showsthe different locations for the conjunctiva, the bulbar conjunctiva 1186lining the eye ball and the palpebral conjunctiva 1188 lining the eyelid internally covering the whole eye lid pocket.

[1011]FIG. 69B shows a cross-sectional side view of the eye lid pocketsinferiorly with an ICL 1190. Superiorly the figure shows the lid pocketin a resting state and a distensible state. The eye lid pocket is quitedistensible and can accommodate a substantially thick device.

[1012]FIG. 69C shows the vascular supply of the lids and conjunctivaincluding facial vessel 1194, supraorbital vessel 1196, lacrimal vessel1198, frontal vessel 1200 and transverse facial vessel 1202. The eye isthe organ with highest amount of blood flow per gram of tissue in thewhole human body. This high vascularization and blood supply providesthe fluid flow and volume for measurement in accordance with the currentinvention. Dashed lines in FIG. 69C mark the eye lid pockets, superiorly1204 and inferiorly 1206.

[1013]FIG. 69D shows a photograph of the palpebral conjunctiva 1207 aand bulbar conjunctiva 1207 b with its blood vessels 1208 a, 1208 b. Theconjunctival vessels 1208 a, 1208 b consists of a multilayered vascularnetwork pattern easily visible through the thin conjunctival epithelium.The structural vascular organization of the conjunctiva creates afavorable arrangement for measurement according to the principles of theinvention since the capillaries lie more superficially, the veins moredeeply and the arteries in between. However considering that theconjunctiva is extremely thin, the distance from the surface isvirtually the same for all three types of vessels. The photograph isbeing used with the sole purpose to clearly illustrate the conjunctivalblood vessels. The bottom part of the figure shows the palpebralconjunctiva 1207 a with the eye lid everted to show the blood vessels1208 a which lines the eye lids internally. Above that one can see thebulbar conjunctiva 1207 b and its blood vessels 1208 b covering the eyeball (white part of the eye). On top of the figure, the cornea 1209 a ispartially shown and the limbal area 1209 b, which is the transitionbetween cornea and conjunctiva.

[1014]FIG. 70A shows an exemplary embodiment of a non-invasive glucosedetection system with the ICL 1220 in accordance with the principles ofthe invention with the ICL being powered by electromagnetic inductioncoupling means 1210 produced at a remotely placed source such as awrist-band 1212 or alternatively the frame of eye glasses.Electromagnetic energy from the wrist-device is transferred to anultracapacitor 1214 in the ICL 1220 which acts as the power source forthe ICL working on a power-on-demand fashion supplying power in turn tothe sensor 1216 which is then activated.

[1015] Subsequent to that, the glucose level is measured by the sensor1216 as an electrical current proportional to the concentration ofglucose in the eye fluid which is then converted into an audiofrequencysignal by the integrated circuit radio frequency transceiver 1218. Theaudiofrequency signal 1222 is then transmitted to the wrist-bandreceiver 1212, with said audiofrequency signal 1222 being demodulatedand converted to an electrical signal corresponding to the glucoseconcentration which is displayed in the LED display 1224 according tothe principles of the invention. Subsequent to that, with the use of amicroprocessor controlled feed-back arrangement, the wrist-band device1212 transdermally 1226 delivers substances from reservoir 1228 by meanssuch as iontophoresis, sonophoresis, electrocompression,electroporation, chemical or physical permeation enhancers, hydrostaticpressure or passively with the amount of substance delivered doneaccording to the levels measured and transmitted by the ICL. Thewrist-band device 1212 besides displaying the glucose level acts as areservoir 1228 for a variety of substances.

[1016]FIG. 70B shows a summary of the system which includes the naturalmotion of looking at a wrist-watch 1229 by eye 1231 to check time 1230which automatically activate the ICL 1233 to transmit the signal 1232and deliver the substance into the user=s skin 1234.

[1017]FIG. 70C shows an exemplary embodiment in which the same steps aretaken as described above with the ICL 1239 located in the lower eye lidpocket 1236 which is remotely activated by signal 1238, but now thedelivery of substances 1244 is done by an ICL 1240 located in the uppereyelid pocket 1242 that acts as a drug reservoir using the sameprinciples as iontophoresis, sonophoresis, electroporation,electrocompression, chemical or other physical enhancers, hydrostaticpressure or passively according to the levels measured. Thecharacteristics of the conjunctiva allows a Therapeutic ICL to deliverchemical compounds in a variety of ways both conventionally (invasive orsimple absorption as with eye drops) and non-conventionally as describedabove.

[1018] The fact that the conjunctiva does not have a high electricalresistance, since the conjunctiva does not have stratum corneum and highlipid content, makes the conjunctiva an ideal place for using ICL drugdelivery system associated with stimulus by electrical energy.Therapeutic ICLs can also contain sensors that detect the chemicalsignature of diseases and cancers before they turn into life-threateningconditions. Once the disease is identified, therapeutic solutions arereleased, for instance smart bombs, which kill, for instance cancercells, according to the chemical signature of the cancer cell. TheTherapeutic ICLs can deliver a plurality of drugs contained inmicrochips according to information provided by the sensor. Although theTherapeutic ICL system is preferably used in conjunction with chemicaldetection, it is understood that the Therapeutic ICLs can work as a drugdelivery system as an isolated unit in accordance with the principlesdescribed in the current invention. Therapeutic is referred to herein asa means to deliver substances into the body using an ICL placed in theeye.

[1019]FIG. 71 shows the flow diagram with steps of the function usingthe system in FIG. 70. The ICL is remotely powered in order to decreasecost and the amount of hardware in the body of the ICL, creating extraspace for a multisensor system. Furthermore, the power-on-demand systemallow the user to have control on how many times to check the glucoselevel according to the prescription by their doctor. Sometimes patientsneed to check only at certain times of the day, this design allows amore cost-effective device for each patient individually. Using anactive system, the ICL can be set to periodically and automaticallycheck the glucose level. Patients who need continuous monitoring canhave a power source in the lens or alternatively with a continuouselectromagnetic coupling derived from a source placed in the frame ofeye glasses. In accordance with the current description at step 1250,the user activates the wrist-watch. Then at step 1252 the user looks athis wrist-watch in the conventional manner to check time. At step 1254the ICL sensor is powered and at step 1256 the sensor is activated withthe analyte measured at step 1258. At Step 1260 the integrated circuitradio frequency transceiver converts the electrical signal into an audiosignal. At step 1262 the wrist-watch converts the audio signal into anumerical value. Step 1264 checks the numerical value acquired againstnormal numerical value stored for the user. At step 1266 substance isdelivered to the user in order to achieve normal range for the user.

[1020]FIG. 72A shows an exemplary embodiment of a microfluidic ICL 2000comprised of a network of microchannels 1270 in communication with eachother and with reaction chambers 1272 and reservoirs 1274. The systemincludes a combination of a microfluidic analysis system and abiosensing system, power source 1276, electrical controller 1278,microprocessor 1280 with an integrated circuit radio frequencytransceiver 1282 and a remotely placed receiver system 1284. The centralelectrical controller 1278 applies electrical energy to any of thechannels 1286, reservoirs 1274 or/and reaction chambers 1272 in whichevaluation occurs according to the application used. With theappropriate electrical stimulus, mechanical stimulus, diffusion or/andcapillary action or a combination thereof, either naturally by the eyeor artificially created, eye fluid and/or cells moves through aselectively permeable membrane into the primary chamber 1288 which is inapposition with the conjunctival surface.

[1021]FIG. 72A also shows wires 1290 and electrodes 1292 which areplaced in contact with the fluid channel 1270, chambers 1272, 1273and/or reservoirs 1274 for applying electrical energy in order to moveand direct the transport of fluid in the network of microchannels 1270with the consequent electrokinetic motion of the substances within theICL microchannel network 2000 according to the application used. The ICLmicrofluidic system includes a control and monitoring arrangement forcontrolling the performance of the processes carried out within thedevice such as controlling the flow and direction of fluid, controllinginternal fluid transport and direction, and monitoring outcome of theprocesses done and signal detection. The dimensions of the microchannelsare in the microscale range on average from 1 μm to 300 μm with themembrane surface in the primary chamber with dimensions around 300 μm indiameter and with the microchannels and chambers containing positiveand/or negative surface charges and/or electrodes in its surface such asfor example thin film electrodes. Electrokinetics are preferably used tomove fluids in the network of microchannels and chambers creating auniform flow velocity across the entire channel diameter.

[1022] Although a pressure-driven system can be used, in this pressuredriven in the system the friction that occurs when the fluid encountersthe walls of the channels results in laminar or parabolic flow profiles.A good example of such flow profile is present in the blood vesselswhich is a laminar flow in a pressure-driven system powered by thepumping function of the heart. These pressure-driven system generatesnon-uniform flow velocities with the highest velocity in the middle ofthe microchannel or blood vessel and close to zero as it moves towardsthe walls.

[1023] As previously described, the microfabrication techniques andmaterials used in the semiconductor industry can be used in themanufacturing of the ICL microfluidic system allowing etching ofmicroscopic laboratories onto the surface of chips made of silicon,glass or plastic with the creation of microchannels which allow uniformflow. The power supply 1276 in combination with the electricalcontroller 1278 according to the application needed delivers electricalenergy to the various electrodes 1292 in the channel network which arein electrical contact with the fluid and/or cells acquired from the eye.In the exemplary embodiment a couple of reaction chambers 1272, 1273 aredepicted.

[1024] Reaction chamber 1272 has a temperature sensor 2002 and reactionchamber 1273 has a pressure sensor 2004, while a pH sensor 2006 isplaced in the wall of the channel in order to detect pH changes as thefluid flows through the microchannel 1270. The signals from the sensorsare coupled to the controller 1278 and microprocessor 1280 by wires 2008(partially shown and extending from electrodes 2202, 2204 and 2006) andradio frequency transceiver 1282 for further processing and transmissionof signal to a remote receiver 1284. The outer ICL structure 2010 worksas an insulating coating and shields the eye environment from thechemical and physical processing occurring in the ICL microfluidicsystem 2000.

[1025]FIG. 72B illustrates the microfluidic ICL placed on the surface ofthe eye laying against the conjunctival blood vessels 2013 with mountedmicrofluidic system 2012, controller 2014, power source 2016 andtransmitter 2020 which are connected by fine wires 2018 (showing onlypartially extending from power source 2016 to the integrated circuitprocessor transmitter 2020 and controller 2014 via wires 2019, alsopartially shown). The signals acquired from the analysis of eye fluidand cells is then transmitted to a remote receiver 2022. The sensingunit 2026 is placed in complete apposition with the conjunctival surfaceand its blood vessels 2024. Although in the schematic illustration thereis shown a small space between the surface of the ICL and theconjunctival surface, in its natural state the surface of the ICL is incomplete apposition with the surface of the conjunctiva due to thenatural tension and force of the eye lid (large arrows 2011). Thusallowing the ICL to easily acquire cells (surface of the eye is composedof loosely arranged living tissue) and/or fluid from the surface of theeye with the cells and/or fluid moving into the ICL microfluidic systemas the small arrows indicate.

[1026]FIG. 73A illustrates an exemplary embodiment of the microfluidicICL 2030 with a network of interconnected microchannels 2032 andreservoirs with reagents with each microcavity preferably containing aseparate testing substance with the microfluidic ICL 2030 in appositionwith the conjunctiva 2052. This exemplary embodiment also includesdisposal reservoir 2034, detection system and ports for electrodes (notshown) as previously described.

[1027] The ICL electrical system applies selectable energy levelssimultaneously or individually to any of the microcavities or channelsby electrodes positioned in connection With each of the reservoirs. Thesubstances present in the reservoirs are transported through the channelsystem with the precise delivery of the appropriate amount of substanceto a certain area or reaction chamber in order to carry out theapplication.

[1028] In accordance with the invention, the fluid and/or cells from theeye are introduced at 2036 into the ICL microfluidic system withmaterials being transported using electrokinetic forces through thechannels 2032 of the ICL microfluidic system 2030. After the eye fluidis introduced in the ICL microchannel network 2032, the fluid ismanipulated to create an interaction between at least two elementscreating a detectable signal. In accordance with the invention, if acontinuous steady flow of eye fluid occurs in the microchannels but nodetectable element is present, then no detectable optical signal isgenerated by optical detection system 2038, thus no signal is acquiredand transmitted. If for instance the immunointeraction creates a changein the optical property of the reaction medium, then the detectablesignal indicates the presence of the substance being evaluated and anoptical signal is generated by optical detection system 2038. Thus adetectable optical signal is created and transmitted. This embodimentincludes a detection zone 2040 for optical detection of for examplechemiluminescent material or the amount of light absorbed using avariety of optical detection systems and laser systems. Exemplaryoptical techniques include immunosensors based on optical detection of aparticular immunointeraction including optical detection of a product ofan enzymatic reaction formed as a result of a transformation catalyzedby an enzyme label as well as direct optical detection of theimmunointeraction and optical detection of a fluorescent labeledimmunocomplex.

[1029] An exemplary embodiment in accordance with the invention showsthe eye fluid 2036 flowing through the microchannel network 2032 fromthe primary chamber 2042 with a certain heart marker (antigen) presentin the eye fluid. Measurement of the heart markers such as for examplePAI-1 (plasminogen activator inhibitor) indicates the risk ofcardiovascular disease and risk of a life-threatening heart attack.Other markers such as troponin T can help identify silent heart damage.Many patients sustain heart attacks, but because of the lack ofsymptoms, the heart damage goes undetected.

[1030] When a second heart attack then occurs with or without symptomsthere is already too much damage to the heart leading then to the demiseof the patient, sometimes described as sudden cardiac death. However, inreality the deterioration of the heart was not sudden, but simplyfurther damage that occurred associated with an undetected initial heartdamage. If silent heart damage was identified, the patient could havebeen treated on a timely manner. If a marker that shows risk for heartdamage before the damage occurs is identified, then the patient can betimely treated and could have normal life. However, a patient at risk ofa heart attack in order to identify a marker for damage has to havedaily monitoring which is now possible with the present invention.

[1031] In accordance with the invention, the eye fluid is transported tothe main channel 2044 and then periodically a certain amount of antibodyto the PAI-1 (antibody) flows from reservoir 2046 into the main channel2044 with the consequent mixing of antigen and antibody and theformation of an antigen-antibody complex considering that the heartmarker PAI-1 (antigen) is present in the eye fluid. The formation of theantigen-antibody complex in the surface of the optical transducer 2048creates a detectable signal indicating the presence of the marker.

[1032] A low-cost exemplary embodiment comprises of simultaneousactivation of a light source 2050 and flow of antibody to the mainchannel 2044. This light source 2050 is coupled to a photodetector 2038and lens. If the marker is present, then the creation of theantigen-antibody complex leads to a change in the amount of lightreaching the photodetector 2038 indicating the presence of the marker.The surface of the optical system 2048 can also be coated with antibodyagainst the antigen-antibody complex which would create a coating of theoptical system 2048 creating a shield with the consequent significantdecrease of light reaching the photodetector 2038 coming form the lightsource 2050. The signal is then transmitted to the user informing themthat the heart marker was detected since there was a signal coming fromoptical detector 2038 and in view of that, the optical system surface iscovered with a specific antibody. Then, the signal generated refers tothe presence of the antigen. Although only one detection system isdescribed, a multiple system can be achieved with detection of multiplesubstances and/or markers simultaneously. Any other fluid or materialcan then subsequently be transported to the disposal reservoir 2034.Although only one exemplary optical detection was described in moredetail it is understood that any optical detection system can be usedfor carrying out the present invention including other opticalimmunosensing systems.

[1033]FIG. 73B shows an ICL microfluidic system 2060 in apposition withthe conjunctiva 2052 with various capabilities in accordance withelectrokinetic principles, microfluidics and other principles of theinvention. The fluid from the eye 2066 is moved into the primarymicrochannel 2062 of the ICL microchannel network 2064 by capillaryaction associated with the mechanical displacement 2070 of fluid by theprotruding element 2068 with further pushing of fluid and/or cells intothe ICL microchannel 2062. The design of this ICL creates an enhancementof flow that may be needed according to certain applications.

[1034] This design with protrusion element 2068 creates a strongapposition of the ICL 2060 against the conjunctival surface 2052. Aninteresting analogy relates to a person laying on a bed of nails inwhich the nails do not penetrate the skin because the force is evenlydistributed along the body surface. If only one nail is displacedupwards the nail will penetrate the skin. The same physical principle ofequal distribution of forces apply to this design.

[1035] The conjunctiva 2052 is a moldable tissue and thin, and the evendistribution of pressure by a smooth ICL surface leads to a certainpermeation rate. However if a protrusion 2068 on the surface of the ICLis created there is an increase in the rate of permeation and capillaryaction due to the surrounding pressure and uneven distribution ofpressure forcing more fluid and cells into the ICL microchannel 2062.This ultra rapid passive flow may be important when multiple substances,fluid and cells are analyzed in a continuous manner such as multiplegene analysis. Most important is that the conjunctival area proves againto be the ideal place for diagnostics with the ICL system since theconjunctiva, contrary to other parts of the body, does not have pressuresensing nerve fibers and thus a patient does not feel the protrusion2068 present in the surface of the ICL, although the protrusion is stillvery small.

[1036] In accordance with the invention, the fluid moves intomicrocavity 2072 which consists of a glucose oxidase amperometricbiosensor. The glucose level present in the eye fluid is then quantifiedas previously described and the glucose level of the sample eye fluid2066 being then identified and transmitted to a remote receiver viamicro lead 2074 (partially shown). Processing then can activateelectrical energy to move the eye fluid 2066 to microcavity 2076 whichcontains an antibody for a certain drug. A reaction antigen-antibodythen occurs in response thereto if the drug being evaluated is presentin the eye fluid collected forming an antigen-antibody complex. The eyefluid with the antigen-antibody complex actively or passively moves tomicrocavity 2078 which contains a catalytic antibody to theantigen-antibody complex. The catalytic antibody is immobilized in amembrane with associated pH sensitive electrodes 2080. Theantigen-antibody complex when interacting with the catalytic antibodypresent in the microcavity promotes the formation of acetic acid with aconsequent change in pH and formation of a current proportional to theconcentration of antigens in this illustration, a certain drug allowingthus therapeutic drug monitoring.

[1037] The exemplary embodiment also includes microcavity 2082 whichcontains immobilized electrocatalytic enzyme and associated electrode2084, which in the presence of a substrate, for instance a certainhormone, produce an electrocatalytic reaction resulting in a currentproportional to the amount of the substrate. Fluid is then moved tomicrocavity 2086 in which a neutralization of chemicals can be achievedbefore leaving the system through cavity 2088 into the surface of theconjunctiva 2090 with the neutralization for instance includingneutralization of pH regarding the potential presence of chemicalsproduced such as remaining acetic acid from cavity 2078.

[1038] The ICL system then can repeat the same process, for example,every hour for continuous monitoring, including during sleeping.Although the amount of acid formed and reagents is minute and the tearfilm washes much more noxious elements, a variety of safety systems canbe created such as selectively permeable membranes, valves,neutralization cavities, and the like. A variety of elements can bedetected with the tests performed by the ICL such as microorganisms,viruses, chemicals, markers, hormones, therapeutic drugs, drugs ofabuse, detection of pregnancy complications such as preterm labor (suchas detecting Fetal Fibronectin), and the like.

[1039]FIG. 73C shows a schematic view of the microfluidic ICL with thenetwork of microchannels 2092 located in the body of the ICLmicrofluidic substrate 2094 and the primary chamber 2096 comprising aprotruding element configuration. It is noted that the microfluidicsystem consists of an ultrathin substrate plate as with a silicon chipbut with a larger dimension in length which fits ideally with theanatomy of the eye lid pockets.

[1040]FIG. 74A shows an ICL 2100 for glucose monitoring placed in thelower eyelid pocket 2102 in apposition to the conjunctival surface andblood vessels 2104 present in the surface of the eye. The exemplary ICLshown in FIG. 74B on an enlarged scale includes in more detail thesensor 2106 for detection of glucose located in the main body of the ICL2100 with its associated power source 2108 and transmitter system 2110.The sensor surface 2106 extends beyond the surface of the remaining ICLsurface in order to increase flow rate of fluid to the sensor andassociated membrane.

[1041]FIGS. 74C and 74E show the eye lid pumping action in more detailmoving fluid toward the sensor 2106 and creating complete apposition ofthe ICL 2100 with the conjunctiva 2112. The presence of the ICL 2100 inthe eye lid pocket 2114 in FIG. 74E stimulates the increase in tensionof the eye lid creating an instantaneous natural pumping action due tothe presence of the ICL 2100 in the eye lid pocket 2114.

[1042]FIG. 74D shows the same ICL 2100 as in FIG. 74B but with anassociated ring of silicone 2120 surrounding the protruding membranearea to better isolate the area from contaminants and surrounding eyefluid.

[1043] The ICL shown in FIG. 75A includes the exposed membrane 2122surrounded by a silicone ring 2120. Although silicone is described, avariety of other adherent polymers and substances can be used to betterisolate the membrane surface from the surrounding eye environment. FIG.75A shows a planar view and FIG. 75B shows a side view. FIG. 75C showsan exemplary embodiment with the whole sensor and membrane being encasedby the ICL 2124. In this case polymers which are permeable to glucosecan be used and the whole sensor and hardware (transmitter and powersupply) is encased by a polymer. The membrane sensor area 2122 encasedin the lens body 2126 can be completely isolated from the rest of thehardware and lens matrix in the body of the lens 2126. In thisembodiment a channel 2128 within the body of the lens 2126 which canhave an irregular surface 2129 to increase flow, is created thusisolating and directing the eye fluid for precise quantification of theamount of glucose entering a known surface of the lens 2130 and reachingthe surface of the membrane sensor 2122 as shown in FIG. 75D. A siliconering 2120 is placed on the outer part of the channel 2128 to isolate thechannel 2128 from the surrounding environment of the eye. By completelyencasing the sensor system, the surface of the ICL covering the membranecan be made with various shapes and surface irregularities. in order toincrease flow, create suction effect, and the like.

[1044]FIG. 76 shows an ICL with optical properties in the center 2140 asin conventional contact lenses, with sensing devices and other hardwareencased in a ring fashioned around the optical center 2140. This ICLincludes a microfluidic system 2142, a biosensor 2144, power supply withcontroller 2146 and transceiver 2148 connected by various wires 2150.

[1045]FIG. 77 shows an exemplary embodiment in which, in contrast to alens system, a manual rod-like system 2160 is used in which the userholds an intelligent rod 2160 which contains the hardware and sensingunits according to the principles of the present invention. The userthen places the sensor surface 2162 against the eye, preferably byholding down the lower eye lid. The sensor surface 2162 then restsagainst the conjunctival surface 2164 and the measurement is done. Sincewith this embodiment the user looses the pump action, friction, andnatural pumping action of the eye lid, the user can, before placing thesensor surface against the eye, rub the opposite side of the sensorwhich in this case would have an irregular surface, in order to createthe flow as naturally produced by the eye lid physiologic action. Thisembodiment can be used by a user who only wants one measurement, let=ssay for instance to check cholesterol levels once a month. Theembodiment also would be useful for holding an enormous amount ofhardware and sensing devices since the rod 2160 can be made in anydimension needed while the lens has to fit within the eye anatomy. Theother advantage of this other embodiment is that there is no need forwireless transmission as the handle itself can display the results. Onemust keep in mind though that this embodiment is not well suited forcontinuous measurement and also would demand an action by the usercontrary to the lens embodiment which measurement takes place while theuser performs his/her daily routines.

[1046] Alternatively, the tip of the rod can be coated with antigen. Thetip is then rubbed or placed against the conjunctiva and/or surface ofthe eye. If antibodies to the antigen are present a detectable signal isproduced, with for instance a variety of electrical signals aspreviously described. The tip of the rod can contain a variety ofantigens and when any one of those is identified by the correspondingantibody a specific signal related to the antigen is produced.Alternatively, the tip can have antibodies and detect the presence ofantigens. Naturally the simpler systems described above can be used inany embodiment such as a rod, contact lens, and the like.

[1047]FIG. 78A shows a two piece ICL in both conjunctival pockets,superiorly 2170 and inferiorly 2172. The ICL placed superiorly includesa microfluidic ICL 2174 positioned against the conjunctival surface withthe eye fluid 2176 moving from the conjunctiva as shown in more detailin FIG. 78B. The fluid and cells 2176 move into the ICL microchannelnetwork in accordance with the eye lid pumping effect and the otherprinciples of the present invention. This exemplary ICL also includes acouple of reaction chambers 2178 and microvalves and membranes 2180within the microchannels.

[1048]FIG. 78C shows in more detail the ICL 2186 placed in the lower eyelid pocket 2172. This exemplary ICL includes a reservoir 2182 which isfilled over time with eye fluid and/or cells 2176 for further processingafter removal from the eye. This embodiment also includes a biosensor2184. Thus said ICL 2186 has a dual function of immediate analysis offluid as well as storage of eye fluid with part of the fluid beinganalyzed in the ICL body with the part of fluid permeating a selectivepermeable membrane 2186 in the surface of the biosensor 2184.

[1049] The ICL in FIG. 79A includes an electroporation system and othermeans to transfer a variety of substances, molecules and ions acrosstissue with increase in permeability of tissues associated with anelectrical stimulus for transport of the substances, molecules and ions.Electrodes in contact with the conjunctival surface 2192 minimallyinvasively remove fluid and/or penetrate surface 2192 with minimalsensation. A variety of fine wires (not shown) can also be used andpenetrate the surface 2192 with minimal sensation. Those systems can bemore ideally used with ICLs and in contact with the conjunctiva 2192than with skin due to the more appropriate anatomy of the conjunctiva2192 as described, compared to the skin since the conjunctiva 2192 is avery thin layer of tissue with abundant plasma underneath. The ICL inFIG. 79B include a physical transport enhancement system 2194 such asapplication of electrical energy and/or creation of an electrical fieldto increase flow of fluid and/or substances into the ICL sensingsystems. The ICL in FIG. 79C includes a chemical transport enhancementsystem 2196 such as an increase of permeation of a variety ofsubstances, such as for example increased flow of glucose with the useof alkali salts.

[1050] Although not depicted, a variety of combinations of ICLs can beaccomplished such as total, partial or no encasement of the sensorsurface and with or without isolation rings, with or without transportenhancers, with or without protruding areas, with or without surfacechanges, and the like.

[1051]FIG. 80 shows a microfluidic chip ICL 2200 which includes a coupleof silicon chips 2202, 2204 in a 5-by-5 array electrode arrangement, areaction chamber 2206 and a disposal chamber 2208. Cells and fluid 2212from the surface of the eye are pumped into the main microchannel 2210with the first chip 2202 electrically separating cells and fluid withsubsequent analysis of substances according to the principles of theinvention. The cellular elements are then moved into the reactionchamber 2206 in which electric current is applied and break the cellwalls with extrusion of its contents. Specific enzymes for organellespresent in the reaction chamber 2206 degrade the proteins and organellespresent but without affecting nucleic acids such as DNA and RNA. Thereleased DNA and RNA can then be further analyzed in the second chip2204 or in a microchannel fluidic system as previously described. Avariety of oligonucleotide probes can be attached to reaction chambers2206 or microcavities in chips 2204 or in chambers in microfluidicsnetwork in order to capture specific nucleic acid with the creation of adetectable signal such as an electrical signal in which an electrode iscoupled with said probe. The ICL technology, by providing a continuousor quasi-continuous evaluation, can identify a mutant gene, for instancerelated to cancer or disease, among a large number of normal genes andbe used for screening high risk populations or monitoring high riskpatients undergoing treatment as well as identifying occult allergiesand occult diseases and risk for certain diseases and reactions to drugsallowing preventive measures to be taken before injury or illness occuror timely treating the illness before significant damage occurs.

[1052] The Human Genome Project will bring valuable information forpatients but this information could be underutilized because patients donot want to be tested with fear of rejection by insurance companies.People with genetic predisposition to certain disorders could have adifficult time to find health insurance and/or life insurance coverage.

[1053] With the prior practices for genetic testing done inlaboratories, patients could be vulnerable to disclosure of theirgenetic profile. Unfortunately, then life-saving genetic informationthat allows early detection and early treatment is not going to be fullyused to the benefit of patients and society in general.

[1054] The ICL system by providing the PIL (Personal InvisibleLaboratory) allows the user to do self-testing and identify geneticabnormalities that can cause diseases in a complete private manner. Thegenetic ICL PIL can, in a bloodless and painless fashion, identify thegenetic predisposition to diseases, and sometimes just a change in dietcan significantly decrease the development of these diseases.

[1055] With the current invention the patient can privately,individually and confidentially identify any disease the patient is atrisk of, and then take the necessary measures for treatment. Forexample, if a patient has genes which are predisposed to glaucoma, ablinding but treatable disease, then the patient can check his/her eyepressure more often and visit eye doctors on a more frequent basis.

[1056] Some cancers are virtually 100% fatal and unfortunately notbecause there is no cure or treatment available but because the cancerwas not timely identified. A devastating example concerns a cancer inthe genitals or cancer of the ovary. This cancer kills virtually 100% ofthe women who are diagnosed with this cancer. It is the highest fatalityrate for all cancers in women and not because there is no cure ortreatment, but because there are no symptoms or signs that would alertthose women to seek medical attention, and even sometimes routineexamination by the doctor does not identify the occult malignancies.

[1057] If a woman knows she has a genetic predisposition for ovariancancer, being privately and confidentiality identified with the ICL PILsystems, the patient can take the necessary preventive steps, be treatedon a timely fashion, and have normal life. A simple small surgery ofjust removing the affected tissue can be curative, compared to thecatastrophic many months of surgeries, chemotherapy and other aggressivetherapies, previously used as a course of treatment still only to delaythe inevitable demise.

[1058] There are many medical situations affecting both men and women,adults and children alike concerning similar situations and diseases asthe described ovarian cancer. In general, the most devastating and fataldisorders are the silent ones, which sometimes are very easy to treat.The current invention thus allows full and secure use of informationprovided by the Human Genome Project in which only the user alone, andnobody else will know about a particular genetic predisposition. Theuser acquires the ICL of interest and places it in the eye and receivesthe signal using a personal device receiver.

[1059]FIG. 81 shows a complete integrated ICL 2220 with a three-layerconfiguration. The top layer 2222 which rests against the conjunctivacontains microchannels, reservoirs, and reaction chambers where thechemical reactions take place. The middle layer 2224 has the electricalconnections and controller that controls the voltage in the reservoirsand microchannels and the bottom layer 2226 contains the integratedcircuit and transmission system.

[1060]FIGS. 82A through 82D shows an exemplary embodiment of animplantable ICL. As mentioned the conjunctiva is an ideal place since itis easily accessible and the implantation can be accomplished easilyusing only eye drops to anesthetize the eye. There is no need to injectanesthetic for this procedure which is a great advantage compared toother areas of the body. It is interesting to note that amazingly theconjunctiva heals without scarring which makes the area an even moreideal location for placement of implantable ICLs.

[1061]FIG. 82A shows exemplary areas for placement of the ICL under theconjunctiva 2232 (area 1), 2234 (area 2) and/or anchored to the surfaceof the eye (area 3) 2236. Implantable ICL 2238 (area 4) uses abiological source such as muscular contraction of the eye muscles togenerate energy. The eye muscles are very active metabolic and cancontinuously generate energy by electromechanical means. In thisembodiment the eye lid muscles or extra-ocular muscles 2240 which lieunderneath the conjunctiva is connected to a power transducer 2242housed in the ICL 2238 which converts the muscular work into electricalenergy which can be subsequently stored in a standard energy storagemedium.

[1062]FIG. 82B shows in more detail the steps taken for surgicalimplantation. After one drop of anesthetic is placed on the eye, a smallincision 2244 (exaggerated in size for the purpose of betterillustration) is made in the conjunctiva. As shown in FIG. 82C, onesimply slides the ICL 2230 under the conjunctiva which by gravity andanatomy of the eye sits in the eye lid pocket, preferably without anyfixation stitches. FIG. 82D shows insertion of the ICL 2246 by injectingthe ICL 2246 with a syringe and needle 2248 under the conjunctiva 2250.The conjunctiva will heal without scaring.

[1063] The location identified in the invention as a source fordiagnostics and blood analysis can be used less desirably in a varietyof ways besides the ones described. Alternatively a cannula can beplaced under or in the conjunctiva and plasma aspirated and analyzed inthe conventional manner. Furthermore a suction cup device can be placedon the surface of the conjunctiva and by aspiration acquire the elementsto be measured. These elements can be transferred to conventionalequipment or the suction cup has a cannule directly connected toconventional analyzing machinery.

[1064] The ICL 2260 in FIG. 83 includes a temperature sensor 2262coupled to a bioelectronic chip 2264 for identifying microorganisms, apower source 2266, a transmitter 2268 and a receiving unit 2270. Whenbacteria reach the blood stream there is usually an associatedtemperature spike. At that point there is maximum flow of bacteria inthe blood. The temperature spike detected by temperature sensor 2262activates bioelectronic chip 2264 which then starts to analyze the eyefluid and/or cells for the presence of bacteria, with for example probesfor E. coli and other gram negatives and gram positives organismsassociated with common infections. The information on the organismsidentified is then transmitted to a receiver allowing immediatelife-saving therapy to be instituted on a timely fashion.

[1065] Previously, nurses had to check the patient=s temperature on avery frequent basis in order to detect temperature changes. Naturallythis is a labor intensive and costly procedure. Then if the nurseidentifies the temperature change, blood is removed from the patient,usually three times in a row which is a quite painful procedure. Thenthe blood has to be taken for analysis, including cultures to detect theorganism and may take weeks for the results to come back. Sometimesbecause of a lack of timely identification of the infectious agents thepatients dies even though curative treatment was available. The ICL thuscan provide life-saving information for the patients. Naturally the ICLtemperature can be used alone as for instance monitoring infants duringthe night with an alarm going off to alert the parents that the childhas a fever.

[1066]FIG. 84 shows a dual system ICL used in both eyes primarily foruse in the battlefield with the ICL 2280 for tracking placed in theright eye and ICL 2282 for chemical sensing placed in the left eye withthe ICL 2280 and/or 2282 placed externally on the eye or surgicallytemporarily implanted in the conjunctiva which allows easy surgicalinsertion and removal of the ICLs as described in FIGS. 82A through 82D.The tracking-chemical ICL system also includes a receiver 2290. Radiopulses 2292 based on GPS technology are emitted from satellites 2284,2286, 2288 in orbit as spheres of position with alternative decoding byground units (not shown) which gives the position of the transceiver ICL2280 placed in the right eye. ICL 2280 can be periodically automaticallyactivated for providing position. If a biological or chemical weapon isdetected by chemical sensing ICL 2282, the receiver 2290 displays theinformation (not shown) and activates the tracking ICL 2280 toimmediately locate the troops exposed. Alternatively, as soon asreceiver 2290 receives a signal concerning chemical weapons, the userscan then manually activate the tracking ICL 2280 to provide their exactposition.

[1067] It is understood that as miniaturization of systems progress avariety of new separation and analysis technologies will be created andcan be used in the present invention as well as a combination of otherseparation systems such as nanotechnology, molecular chromatography,nanoelectrophoresis, capillary electrochromatography, and the like. Itis also understood that a variety of chips, nanoscale sensing devices,bioelectronic chips, microfluidic devices, and other technological areaswill advance rapidly in the coming years and such advances can be usedin the ICL system in accordance with the principles of the invention.

[1068] The ICL PIL systems allow any assay to be performed and anysubstance, analyte or molecule, biological, chemical or pharmacologicaland physical parameters to be evaluated allowing preventive and timelytesting using low-cost systems while eliminating human operatorsinvolved in hazardous activities including the accidental transmissionof fatal diseases such as AIDS, hepatitis, other virus and prions, andthe like.

[1069] Contrary to the prior art that has used non-physiologic andnon-natural means to perform diagnostics and blood analysis with meanssuch as tearing and cutting the skin with blades and needles, shocking,destroying tissue electrically or with lasers, placing devices in themouth that can be swallowed and have no means for natural apposition,and so forth, the present invention uses placement of an ICL in andisturbed fashion in order to acquire the signal, with the signal beingphysiologically and naturally acquired as the analytes are naturally andfreely delivered by the body.

[1070] If one thinks about the conjunctival area and sensors accordingto the principles of the invention, and consider that the area not onlyhas superficial blood vessels, but also has fenestrated blood vesselswith plasma pouring from the lumen through the holes in the vessel wall,one would appreciate the ideal situation of the present invention.However, further, the blood vessels are easily accessible, no keratin ispresent and also living tissue is present on the surface allowingcomplete fluid and cell analysis. Moreover a very thin and permeableepithelium associated with a very homogeneous thickness throughout itswhole surface is available with the direct view of the blood vessels.Also, natural eye lid force acts as a natural pump for fluid.

[1071] Furthermore, sensors are placed in natural pockets, and there isnot just one small pocket, but four large pockets with over 16 squarecentimeters of area that can be used as a laboratory. In this pocket asensor can be left completely undisturbed without affecting the functionof the eye and due to high oxygen content in the surface of theconjunctiva the ICL can be left in place for long periods of time, evena month based upon material currently available for long-term use in theeye. In addition, the area is highly vascularized, and the eye has thehighest amount of blood per gram of tissue among all organs in the humanbody. Furthermore, it provides not only chemical parameters, but alsothe ideal location for physical parameters such as measurement oftemperature since it gives core temperature, pressure and evaluation ofthe brain and heart due to the direct connection of the eye with thebrain and the heart vasculature and innervation. In addition, the areais poorly innervated which means that the patient will not feel the ICLdevice that is placed in the pocket, and the lid supports the devicenaturally with an absolutely cosmetically acceptable design in which theICLs are hidden in place while non-invasively providing life-savinginformation.

[1072] The ICL PIL offers all of that plus time-savings andeffort-savings allowing users to take care of their health while doingtheir daily activities in a painless fashion and without the userspending money, time and effort to get to a laboratory and without theneed to manipulate blood associated with benefits of decreasing harm byillnesses, preventing life-threatening complications by variousdiseases, timely identifying cancers and other diseases, monitoringglucose, metabolic function, drugs and hormones, calcium, oxygen andother chemicals and gases, and virtually any element present in theblood or tissues, detecting antigen and antibodies, locating troopsexposed to biological warfare, allowing timely detection and treatment,temperature detection with simultaneous detection of microorganisms,creation of artificial organs and drug delivery systems, and providingmeans to allow full and secure use of information by the Human GenomeProject, ultimately improving quality of life and increasinglife-expectancy while dramatically reducing health care costs. The ICLPIL thus accomplishes the rare feat in medical sciences of innovationassociated with dramatic reduction of health care costs.

[1073]FIG. 85 shows a schematic block diagram of one preferredreflectance measuring apparatus of the present invention. The systemincludes a radiation source 2300 emitting preferably at least onenear-infrared wavelength, but alternatively a plurality of differentwavelengths can be used. The light source emits radiation 2302,preferably between 750 and 3000 nm, including a wavelength typical ofthe absorption spectrum for the substance of interest. The radiation isthen filtered and focused by the optical interface system 2304 ontofiber optic cable 2306 which transmits the radiation to theplasma/conjunctiva interface 2310. The plasma/conjunctiva interface 2310is comprised of the thin conjunctiva lining 2320 with plasma interface2330 and a substance of interest 2350 underneath said conjunctiva 2320.Optic fiber cable 2306 is part of a dual optic fiber cable systempreferably with fiber cable 2306 and collecting fiber cable 2312 locatedside-by-side. The diameter of the optic fiber is 300 μm, although avariety of diameters can be used.

[1074] The radiation is directed at the plasma interface 2330 anddelivered via sensor head 2314 in apposition to conjunctival lining2320. The plasma 2330 is present between the thin conjunctival lining2320 and the sclera 2316, a white and water free structure which is theexternal layer of the eyeball. In addition, it is understood that thereare areas in the eye which the plasma is interposed between theconjunctiva and ligaments or other tissues but not the sclera, as itoccur in areas in the cul-de-sac (not shown).

[1075] The optic fiber 2306 delivers the radiation 2302 provided by thesource 2300 to the plasma interface 2330. The radiation 2302 directed atthe plasma 2330 is partially absorbed and scattered according to theinteraction with the conjunctival lining 2320 and the substance ofinterest 2350 present in the plasma 2330. Conjunctiva 2320 is the onlytissue interposed between radiation 2302 and the substance of interest2350. The conjunctiva 2320 does not absorb near-infrared light andscattering is insignificant as the conjunctiva is an extremely thinmembrane. Part of the radiation 2302 is then absorbed by the substanceof interest 2350 and the resulting radiation emitted from the eyecorresponds to said substance of interest 2350.

[1076] The resulting radiation from the eye is reflected back andcollected by collecting optical fibers 2312 via sensor head 2314 anddelivered to the detector 2318. The system includes a spectrumanalyzer/detector 2318 for detecting and analyzing radiation 2302emitted by the radiation source 2300 and which has interacted with theplasma interface 2330 with said resulting radiation containing spectralinformation for the substance of interest 2350. The resulting radiationis converted into a signal by the spectrum/analyzer/detector 2318 whichcan be amplified and converted to digital information by the A/Dconverter 2322. The information in then fed into a processor 2324 andmemory 2326 for analyzing the spectral information contained therein andcalculating the concentration of at least one chemical substance in theeye fluid derived from the resulting spectral information.

[1077] The concentration of the substance of interest 2350 isaccomplished by detecting the magnitude of light attenuation collectedwhich is caused by the absorption signature of the substance ofinterest. Models, calibration procedures, and mathematical/statisticalanalysis such as multivariate analysis and PLS can be used to determinethe concentration of the substance of interest 2350 from the measuredabsorption spectrum.

[1078] Data analysis by empirical or physical methods previouslymentioned can be used for analysis of the resulting spectra associatedwith signal processing and which are performed by the processor 2324including Fourier Transformation, digital filtering, and the like.Algorithm or other analyses are employed to compensate for thebackground response, noise, source of errors, and variability. Since thespectral information according to the principles of the invention hasvery few interfering factors, statistical extraction of the spectra ofinterest is facilitated allowing accurate determination of theconcentration of the substance of interest 2350.

[1079] Processor 2324 can contain or be connected to a memory unit 2326which can store data related to calibration, patient's measurement data,reference data, suitable algorithms, and the like. Display part 2328 isadapted to output results of the concentration of the substance ofinterest by the processor. The processor 2324 can also be connected toan audio transmitter 2334, such as a speaker, which can audiblycommunicate abnormal levels, and to a device 2332 for delivery ofmedications according to the concentration of the substance of interest2350.

[1080] Since the present invention reduces or eliminates the interferingelements and background interference such as fat, melanin, skin texture,and the like as previously described, the value indicative of theresulting spectra and data analysis accurately and precisely determinethe concentration of the substance of interest 2350.

[1081] A variety of radiation sources 2300 can be used in the presentinvention including LEDs with or without a spectral filter, a variety oflasers including diode lasers, halogen lights and white light sourceshaving maximum output power in the near infrared region with or withouta filter, and the like. The radiation sources 2300 have preferablyenough power and wavelengths required for the measurements and a highspectral correlation with the substance of interest 2350. The range ofwavelengths chosen preferably corresponds to a known range and includesthe band of absorption for the substance of interest 2350.

[1082] Light source 2300 can provide the bandwidth of interest with saidlight 2302 being directed at the substance of interest 2350. A varietyof filters can be used to selectively pass one or more wavelengths whichhighly correlate with the substance of interest 2350. The lightradiation 2302 can be directly emitted from a light source 2300 anddirectly collected by a photodetector 2318, or the light radiation 2302can be delivered and collected using optic fiber cables. An interfacelens system can be used to convert the rays to spatial parallel rays,such as from an incident divergent beam to a spatially parallel beam.

[1083] When a laser light or a continuous wavelength source is employedan optical interface may not be necessary as one single optical path isderived from the source 2300. The output of a white light source, somelasers, and the like can be coupled directly into the receiving end ofoptical fibers which can be used as a light pipe. Due to the samplecharacteristics of the conjunctiva/plasma interface 2310 as previouslydescribed, the system can use a variety of diodes and detectors beyond2500 nm allowing more spectrum regions to be used which in turnfacilitate the accurate measurement of the substance of interest 2350.

[1084] Wavelength selection means can include bandpass filters,interference filters, a grating monochromator, a prism monochromator,acousto-optic tunable filter, or any wavelength dispersing device.Although dual optical fibers were used in the illustration, it isunderstood that direct light sources and direct collection detectors canbe used as well as a single fiber optic bundle that transmits radiationto the conjunctiva 2320 and collects resulting radiation from saidconjunctiva 2320. A variety of amplifiers, pre-amplifiers, and filtersand the like can be used for reducing noise, amplifying signals,filtering, smoothing, and the like. Although an amplifier can be used asdescribed, it is understood that amplification is secondary for theoperation.

[1085] Now referring to FIG. 86, the apparatus includes a probe 2336with a sensor head 2314 provided on its end with radiation sourcetransmission fiber 2338 and radiation receiving collector fiber 2342which are preferably side-by-side. The distance between the radiationtransmission source 2338 and the radiation receiving collector 2342 ispreferably around 0.5 mm, but determined such that the light path 2340is mostly formed in the plasma interface 2330. Although only onecollecting fiber 2342 is illustrated, it is understood that a pluralityof collection fibers positioned at different distances from the sourcefiber 2338 can be used. Use of optical fibers enable optimization ofdelivery with the light 2346 being piped through optical fibers 2338 anddelivered to the plasma/conjunctiva interface 2310.

[1086] Still with reference to FIG. 86, the end of source fiber 2338directs radiation at the plasma interface 2330 where there is a highrelative concentration of the substance of interest 2350. The radiation2340 interacts with the substance of interest 2350 and the resultingradiation 2348 is collected by the collection fibers 2342 for subsequentmeasuring absorbencies at a wavelength selected for the substance ofinterest 2350 and determining the concentration of said substance ofinterest 2350. The sensor head 2314 can include a wall 2344 positionedbetween the light source 2338 and light collector 2342 to shield thecollector 2342 from light 2346.

[1087] In a transparent, thin, and homogeneous structure like theconjunctiva/plasma interface 2310, Beer-Lambert's' law can be applied todetermine energy absorption.

[1088] As an example, glucose can be chosen as a substance of interestmeasured in the conjunctiva/plasma interface in accordance with apreferred embodiment of the invention. Near-infrared reflectancemeasurement of plasma glucose adjacent to the conjunctiva was done inassociation with conventional methods normally used in a laboratory toevaluate plasma glucose. The “overall setup” includes:

[1089] 1. A light source generating multiple wavelengths of nearinfrared light.

[1090] 2. Fiber optics. Fiber optics transmits the photons from thelight source to the conjunctival site on the patient and from theconjunctival site to a detector. In general photons follow an ellipticalpath through the sample from the source to the detector. Fiber opticseparation is important in determining the area of interrogation by theincident photons. The shorter the interoptode distance, the less deep isthe penetration of light. In the probe arrangement (sensor head) for theconjunctiva, the optic fibers were separated by a distance of 0.5 mm.Alternatively, a distance of 0.1 mm was used for interrogatingsubstances present in the superficial structure of theconjunctiva/plasma interface and thinner interface areas. The collectingoptic fiber collected the resulting radiation. The resulting radiationcontains spectral information for each plasma constituent and due to itsoptimal point of detection as disclosed in the invention there, is nosignificant background spectral information.

[1091] 3. Selective filters or diffraction grating systems. These filtersystems are used for selecting wavelength of interest as well aseliminating wavelength which do not have a high correlation with thesubstance of interest. A reference filter can be used and consists of anarrow bandpass filter which pass wavelengths which have no correlationwith the substance of interest.

[1092] 4. Photon detection circuitry such as a photomultiplier andintegration amplifier including a lead-sulfide photodetector whichconvert the resulting radiation into signals representative of theintensity of those wavelengths.

[1093] 5. An A/D converter to convert the analog signals from the photondetection circuit to digital information.

[1094] 6. A central processor with appropriate software (algorithms) toprocess the information obtained in the resulting radiation and compareit with the known amount of reference radiation.

[1095] 7. An information display system to report the result.

[1096] A known amount of incident light is used to illuminate theconjunctiva using a probe in apposition to the conjunctiva. The amountof light recovered after the photons pass through the conjunctiva dependon the amount of light absorption by the substance of interest and thedegree of light scatter and absorption by the tissue. Scattering as wellas absorption by tissue and other interfering constituents areinsignificant in the conjunctiva as previously described.

[1097] In more detail, the testing equipment included a 75 W halogenlight source coupled to an optic fiber (available from Linos PhotonicsGmbH, Göttingen, Germany). An optical filter adjusted the wavelength toprovide near-infrared radiation in the 1400-2500 nm spectral range. Theradiation was delivered to the conjunctiva surface using a fiber opticprobe arrangement (sensor head) supported by a Haag-Streit Goldmanntonometer piece and associated Haag-Streit slit-lamp 6E (Haag-Streit,Bern, Switzerland).

[1098] The sensor head was coupled to the conjunctival surface of theeye. Reflected radiation that interacted with the conjunctiva wascollected by the collecting optic fiber. The optic fiber delivered theresulting radiation to a photodetector analyzer which performed thequantitative analysis.

[1099] The magnitude of the absorption peak is directly related to theconcentration of glucose. Suitable analyzers include modified FourierTransform Infrared (FTIR) spectrometers with chemometric softwarepackages. Those are available from the PerkinElmer Corporation(Wellesley, Mass.) and Thermo Nicolet Company (Madison, Wis.).

[1100] The signal was digitized and the concentration of conjunctivalplasma glucose determined by chemometric analysis algorithms withcomparison of the unknown value with a standard reference to determinethe conjunctival plasma glucose value. Blood was acquired and plasmaglucose measured with conventional laboratory analysis using a Beckmananalyzer system.

[1101] The mean value of conjunctival plasma glucose was 101.2 mg/dl anda correlation coefficient of 0.94 was achieved when compared to physicalvalues by laboratory testing. The FTIR used allows evaluation of allincident wavelengths. The signal processing of the FTIR system canselect for the final analysis the wavelength related to the substance ofinterest. Various substances of interest such as glucose, cholesterol,ethanol, can then be evaluated by using the different algorithms foreach substance incorporated in the FTIR system.

[1102] Alternatively, a custom made system, as described in the “overallsetup” above, was constructed using the above light source and selectivebandpass filters centered around 2100 nm (available from CVI LaserCompany, Albuquerque, N. Mex.) for selecting the wavelength for glucose.This alternative embodiment, provides a lower-cost and more compactsystem, but is capable of measuring only one substance of interestaccording to the wavelength selected.

[1103] In-vitro calibration models available commercially can be usedaccurately and precisely as a reference since there is no backgroundinterference. However, a simplified calculation and statistical methodcan be achieved since the conjunctiva/plasma sample obeys Beer-Lambertlaw and the background variables are eliminated. The resulting radiationacquired from the conjunctiva corresponds directly to plasmaconstituents. A quantitative measure of the glucose concentration usingthe resulting absorption intensity can be provided upon calculationusing Beer-Lambert's law.

[1104] In addition, an in-vivo calibration method is used. Theconcentration of plasma glucose is obtained by invasive means andanalyzed in the conventional laboratory setting. The range of glucoselevels of usual interest in clinical practice (40 to 400 mg/dl) obtainedinvasively creates a reference database, which is then correlated to theresulting radiation obtained using conjunctival plasma. Considering astable optical system as the conjunctiva/plasma interface, the amount ofincident radiation (known) and the subsequent reflected radiation(measured) can be calculated for each wavelength related to thesubstance measured creating then a reference line. The concentration ofthe substance of interest is then determined by correlating thepredicted value with the acquired (unknown) value using thepredetermined calibration line.

[1105] An alternative embodiment and experiment involved usingAttenuated Total Internal Reflection technique and incident radiation inthe 9,000 to 10,000 nm wavelength region. This spectral region has highcorrelation with glucose and is strongly absorbed by glucose whileavoiding absorption by interfering constituents. However this region isnot used because large amounts of energy are needed which can causedamage to the tissue. The large a mount of energy is needed because thesample of interest (glucose) is located deep and the far-infrared energyis readily absorbed by interfering constituents. Thus the radiationenergy does not reach the substance of interest (glucose) present deepin the tissues.

[1106] Contrary to that, in the present invention a low powerfar-infrared incident radiation was used due to the insignificantabsorption due to the characteristics of conjunctiva/plasma interface(as disclosed in the invention) and the plasma with glucose is presentin the surface. Thus, no damage or discomfort was elicited duringmeasurement. The conjunctiva/plasma interface allows measurement to bedone in this region of the wavelength spectrum because the substancebeing interrogated is already separated and present in plasma in thesurface of the sample.

[1107]FIG. 87 shows a schematic block diagram of one preferredembodiment of the present invention with wireless transmission ofinformation to an external receiver. The apparatus includes a sensorhead 2352 which has a light source 2354 such as LED and a lightcollector 2356 such as an optic fiber cable which is connected to aphotodetector 2358. Radiation is transmitted from the source 2354 anddirected at the plasma interface 2330, between the conjunctiva 2320 andsclera 2316. The resulting radiation is reflected back and collected bycollecting optic fiber 2356 and transmitted to photodetector 2358. Thesignal is then converted to digitized information by the A/D converter2360 and sent to the RF transceiver 2362 with the signal 2366 beingtransmitted to a remotely placed RF transceiver 2364.

[1108] The signal is then fed into the processor 2368 and memory 2376which calculates the concentration of the substance of interest 2350which is subsequently visualized in display 2370. The processor can alsoactivate an alarm and audio transmitter 2372 that can alert the userabout abnormal measurement levels and control the delivery of medicationthrough delivery device 2374. The delivery device 2374 can include:contact lens dispensing systems, iontophoresis-based dispensing systems,infusion pumps as insulin infusion pump, glucagon pump for injection ofglucagon when glucose levels are below 55 mg/dl, drug infusion devices,inhalers, and the like. The processor 2368 can make adjustments fordelivery of medication through delivery device 2374 according to theidentification or concentration of the substance of interest 2350.

[1109]FIG. 88 shows the front surface of the eye with cornea 2378, iris2382, and conjunctival vessels 2380. The upper 2384 and lower 2386eyelids were pulled away to show the conjunctival lining 2320 coveringthe eye surface and the substance of interest 2350 present in thesurface of the eye. Most of the conjunctival area 2320 is hidden in theeyelid pocket both superior and inferior and not observable by anexternal viewer.

[1110]FIG. 89(A) shows schematically a reflectance measuring system 2388encased in the contact device 2390, the combination of which is referredto herein as a measuring Intelligent Contact Lens (ICL). The measuringICL is placed in the eyelid pocket 2392 in apposition to theconjunctival lining 2320. The measuring ICL includes a sensor head 2314with light source 2394 and light detector 2396, RF transceiver 2402 andother electronics 2398 previously described.

[1111]FIG. 89(B) shows in more detail the sensor head 2314 in appositionto the conjunctiva 2320 in the cul-de-sac 2404. The radiation emittedinteracts with the substance of interest 2350 present underneath theconjunctiva 2320. Source 2394 and detector 2396 are mounted adjacent toeach other in a way that light from the source 2394 reaches thesubstance of interest 2350 and is received by the detector 2396.

[1112]FIG. 89(C) shows a cross-section view of the eye and eyelid 2410with the measuring ICL 2400 and its light source 2394 and lightcollector 2396 in apposition to the cul-de-sac 2404 of the conjunctiva2320 which is free of blood vessels but has plasma 2330 collectedunderneath. FIG. 89(C) also shows another position for light source 2394a and collector 2396 a as in apposition to the bulbar conjunctiva 2406.

[1113]FIG. 89(D) shows a bird's eye view of the eye surface with cornea2378, iris 2382, conjunctival vessels 2380, and measuring ICL 2400 inapposition to the conjunctiva 2320 and substance of interest 2350. Thethickness of the measuring ICL 2400 is preferably less than 5 mm.

[1114] The contact device or measuring ICL 2400 allows appropriateinterface with the sample in a reproducible location and with areproducible amount of pressure and temperature on the sample surface.Normal eyelids exert a stable amount of pressure against the measuringICL 2400 when the eyelid 2410 is in a relaxed state, meaning withoutsqueezing the eyelids. The pressure applied by the eyelid 2410 in theresting state is fairly constant and equal in normal subjects with ahorizontal force of 25,000 dynes, a tangential force of 50 dynes andpressure of 10 Torr. Muscles in the body can enlarge and become strongerby means of continuous exercising such as in body building. Contrary tothat, the muscles in the eyelids have a special characteristic and donot hypertrophy by continuous blinking or eyelid exercising. The musclesin the eyelid remain with similar contractility and force throughoutlife unless affected by a disease. This similar and stable eyelidcontractility and tone allows an ideal apposition of a source detectorpair to the tissue surface. Positioning of the conjunctiva 2320 inapposition to the sensor head 2314 with the source-detector pair can bedone naturally by the eyelid which leads to great reproducibility andreproducible degrees of pressure with very low inter- andintra-individual variability.

[1115] The eyelid pocket 2420 also provides good reproducibility as faras location of the measurement since the measuring ICL 2400 can be madeto fit a particular pre-determined area of the eyelid pocket 2420allowing to reproduce the same location for measurement. The eyelidstructural arrangement provides the only superficial area in the body inwhich a true pocket is formed creating a natural confined environment inthe surface of the body by said pocket. The conjunctiva as mentioned isa thin homogenous tissue located in a naturally confined area of thebody forming a natural pocket and the lens dimensions can assure thatthe same site is taken for different measurements and centered on areasof high plasma 2330 concentration and minimal blood vessels such as inthe lower part of the cul-de-sac 2404. Alternatively, the light 2302 canbe directed to any point in the conjunctiva 2320.

[1116] The embodiments of the present invention provide a reproducibleand stable degree of pressure and reproducible location which isachieved naturally according to the morphology and physiology of the eyeand eyelids.

[1117] A contact device for placement on the surface of the eye andpreferably in the eyelid pocket as shown in FIG. 101B was used. Thecontact device preferably contains an infrared LED (available fromPerkinElmer Corporation) as a light source. Infrared LEDs(wavelength-specific LEDs) are the preferred light source for theembodiment using a contact device because they can emit light of knownintensity and wavelength, are small in size, low-cost, and the light canbe precisely focused in a small area of the conjunctiva. By using aninfrared LED that emits a narrow bandwidth of radiation no filters areneed to be coupled with the photodetector.

[1118] Alternatively, a miniature selective filter that transmits lightwithin the 2,100 to 2,200 range of wavelengths is incorporated with thephotodetector. The selective filter transmits wavelength whichcorresponds to absorption by glucose.

[1119] The preferred photodetector included a semiconductor photodiodewith a 4001 μm diameter photosensitive area coupled to an amplifier asan integrated circuit. The photodetector has spectral sensitivity in therange of the light transmitted. The photodetector receives an attenuatedreflected radiation and converts the radiation into an electricalsignal. The photodetector is connected to a low-power radio-frequencyintegrated circuit and the electrical signal is converted into an audiosignal and transmitted to an external receiver.

[1120] An alternative embodiment used an A/D converter and a digital RFintegrated circuit built in the contact device. The RF circuit thentransmits the analog or binary signal corresponding to the intensity ofradiation (resulting radiation) reflected from the conjunctiva/plasmainterface. The remote RF transceiver receives the signal and sends it toa processor for signal processing and calculation of the concentrationof glucose using a predetermined calibration reference. The detectoroutput data is correlated to blood glucose levels using FTIR andstatistical analysis previously described. Although one LED wasdescribed, multiple miniature LEDs can be used as light sources forsimultaneous measurement of multiple substances using multiple pairsource/detector.

[1121] Besides active RF transmission, passive RF devices built-in inthe contact device can be used and receive the signal from the sensor.An external radiating antenna emits the excitation energy which powersthe contact device. Such passive RF devices includes paper thininductive and capacitive designs, for example Performa tags availablefrom Check Point Systems, Inc. Thorofare, N.J. and BiStatix tagsavailable from Motorola Inc., Schaumburg, Ill.

[1122]FIG. 90 shows a schematic block diagram of one preferredtransmission measuring apparatus of the present invention. In anexemplary embodiment, the system includes a source of light 2430 whichemits light at a plurality of different wavelengths and a photodetector2440 for detecting light 2432 emitted from said source 2430. The source2430 and the detector 2440 are arranged diametrically opposed to eachother and preferably including a forceps configuration. The arrangementis such that the light output 2432 from the source 2430 interacts withthe eye fluid and substance of interest 2350 before being collected bythe detector 2440. The resulting transmitted radiation 2434 includes theemitted radiation less the back scattered and absorbed radiation plusany forward scattering radiation. Since in the present invention thereis insignificant scattering due to interfering constituents, theresulting radiation 2434 is the known emitted radiation less theabsorbed radiation which corresponds to the substance of interest 2350.The resulting radiation 2434 is collected by the detector 2440 andcontains the spectra of the eye fluid at each of the selectedwavelengths. Since in the present invention the scattering isinsignificant and there is a high signal, a small number wavelength isrequired and the resulting spectra relates to the substance of interest2350. The resulting transmitted spectra is then converted by the A/Dconverter 2436 into digital information and the spectral informationobtained is sent to the processor 2438 for spectral analysis todetermine the concentration of the substance of interest 2350. Theprocessor 2438 can be connected to a display 2442 for reporting theconcentration of the substance of interest, to an alarm system 2444 tobring attention to abnormal and ominous values and to a medicationdelivery system 2446 which delivers medication according to theconcentration of the substance of interest.

[1123] In reference to FIG. 91(A), the radiation source fiber 2448 andcollector fiber 2452 are positioned diametrically opposed to each otherso that the output of the radiation source 2448-goes through theplasma/conjunctiva interface 2450 before being received by the collector2452 and then sent to the detector (not shown). The space X from theradiation source 2448 to the collector 2452 can be changeable but isultimately fixed in order to maintain a fixed optical distance betweensaid source 2448 and collector 2452.

[1124] In one exemplary embodiment the distance X in the tip of theforceps device, meaning the distance between the light source and thelight detector is preferably 1 mm, however various optical pathdistances that encompass the sample 2450 with the substance of interest2350 can be used. The source can include the output end of an opticalfiber cable connected to a light radiation source or a plurality ofradiation sources. The detector can include the receiving end of acollection of optical fibers connected to one or a plurality ofphotodetectors.

[1125] Optical fibers encased in each arm of the forceps device arepreferably used as a light delivery 2448 and light collection 2452system for the light source and the light detector providing a moreergonomic design for the forceps configuration device. Duringmeasurement the conjunctiva/plasma interface 2450 is placed between thepath of the optical beam from the source 2448 to detector 2452. Theoutput of the light source and the input of the detector are in contactwith the plasma/conjunctiva interface 2450 or in close proximity to suchinterface.

[1126] FIGS. 91(B) and 91(C) show alternative embodiments for thesource-collector pair for exemplary transmission measuring systems. FIG.91(B) shows rigid arms 2454 connecting the light source end 2448 to thelight collector end 2452 at a fixed distance X with plasma 2330interposed between the two ends 2448, 2452. Although two arms, superiorand inferior, are shown, it is understood that only one rigid arm isneeded to keep distance X as a fixed distance.

[1127]FIG. 91(C) shows an alternative embodiment in which rigid arms2458 are connected to semi-permeable membranes 2456. The membranes 2456can be made permeable only to the substance of interest 2350 which thencan enter a chamber 2460 formed by the membranes 2456 and interact withthe radiation emitted by the light source 2448. The membranes 2456 canbe coated with permeability enhancers which can enhance the flow of thesubstance of interest 2350 to the measuring chamber 2460. Rigid ends atprefixed distance X are used to maintain light source 2448 and collector2452 at a prescribed space to define a measuring optical path length.The radiation from the source passes through the optical fiber 2448which works as a guide path to the light. The radiation then interactswith the substance of interest 2350 selectively present in the samplefluid in the chamber 2460. The resulting radiation is incident upon thelight receiving end and guided to the detector through fiber opticcollector 2452. The embodiments of FIGS. 91(B) and 91(C) are bettersuited to use as an implantable measuring system.

[1128]FIG. 92 shows schematically one of the preferred embodiments usinga forceps-like probe 2470 with wired transmission of resulting radiationsignal to the processor 2468. The apparatus includes a main body housing2472 which encases the light source 2462, photodetector 2464, A/Dconverter 2466, and a processing/controlling part 2468. In thisexemplary embodiment, the light source 2462 and photodetectors 2464 canbe located in the main body 2472 away from the forceps-like probe 2470.The main body housing 2472 is connected to the forceps-like probe 2470by cable 2474 which contains fiber optics from the light source 2462 andfiber optics to the photodetector 2464. The forceps-like probe 2470configuration includes spatially separated pairs of infrared lightdelivering fibers 2476 and light collecting fibers 2478. Arms of theforceps-like probe 2470 are moveable toward and away from each other.The gap between delivering fibers 2476 and collecting fibers 2478 can beadjusted into a fixed 1 mm position by a mechanical stop part 2480.

[1129] The conjunctival tissue and plasma are placed or grasped betweenthe two faces of the infrared light source end 2476 and the infraredlight detector end 2478 in the arms of the forceps 2470. The lightsource 2462 emits radiation which is focused onto fiber optic cable2476. Each source and collector pair is spaced so that light from thelight source 2462 and fiber optic cable 2476 passes through theconjunctiva/eye fluid interface (not shown) and is received by thecollecting optic fiber cable 2478. The resulting radiation output of thecollection optic fiber cable 2478 is provided through a second opticalinterface system to a the analyzer/detector 2464 housed in the main bodyhousing 2472 of the unit. The signal is then converted to digitalinformation by AID converter 2466 and fed into the processor 2468 fordetermination of the concentration of the substance of interest.

[1130] A modified forceps probe similar to the one illustrated in FIG.92 was used for transmission measurements. Conjunctiva in the cul-de-sacwas grasped by the forceps. A halogen light source delivered radiationto the conjunctiva coupled to the input end of optic fibers in the armof the forceps. The radiation passed through the interfaceconjunctiva-plasma-conjunctiva with the optical path set at 1 mm. Thecollecting fibers sent the resulting radiation to a detector associatedwith a narrow bandpass filter centered at 2120 nm to separate theglucose band. The digitized signal was fed to the processor. Theprocessor is programmed to calculate the concentration of glucose usinga calibration line obtained by a PLS regression analysis and a 0.93correlation coefficient was obtained.

[1131] Alternatively as shown in FIG. 93(A) the measuring device 2482can be implanted under the conjunctiva 2320 with said device 2482 beingbathed by the surrounding plasma. In such embodiment the device 2482 isencased in biocompatible material as previously described with theoptical surfaces encased by infrared transitive material such assapphire or high-grade quartz. The system includes a main body 2484 andtwo arms located diametrically opposed to each other encasing the lightsource 2486 and detector 2488. The light detector 2488 collects thelight emitted from the light source 2486 after it interacts with thesubstance of interest 2350.

[1132] During measurement the plasma 2330 located between the lightsource and detector is the source medium for measuring the substance ofinterest 2350 as shown in the enlarged view of FIG. 93(B). Thedimensions of the detector 2488 are such that allows optimal acquisitionof the light signal emitted from the light source 2486 with the detector2488 being reactive to the spectrum of collected wavelengths for thesubstance of interest 2350. The output signal is converted into anelectrical signal which is then transmitted as an audio signal by RFtransceiver 2490 to a remotely placed receiving unit 2492. The signal isthen converted by the A/D converter 2494 and then analyzed and processedby the analyzer/processor 2498 for obtaining the concentration of thesubstance of interest 2350 which is reported by display 2496, activatesan audio transmitter 2502 that can alert the user about abnormalmeasurement levels, and controls the delivery of medication through amedication delivery device 2504 according to said measurement. Thesystem can alternatively include a detector and A/D converter in themain body with the output signal of the detector being received by theA/D converter which converts the signal into digital information whichis transmitted by RF transceiver to remotely placed RF transceiver.

[1133] Alternatively as shown in FIG. 94 the measuring device 2500 canpenetrate the conjunctiva 2320 with one of its arms 2508 locatedunderneath the conjunctiva lining and the other arm 2506 located abovethe conjunctival lining 2320. The conjunctiva 2320 can be easilypenetrated with a very mildly sharp point or even a blunt end. Light isemitted through the conjunctiva 2320 by arm 2506 and collected by theopposing arm 2508. The conjunctiva is the only superficial area in thebody that an incision can be done using only one drop of topicalanesthetic. Although, less desirable, a reflector for infrared light canbe implanted under the conjunctiva.

[1134] A further alternative embodiment as shown in FIG. 95(A) includesa forceps 2510 configuration to be used for grasping the edge of theeyelid 2410, shown in a cross-section of the eye and eyelid. The forceps2510 of FIG. 95(A) is shown in the enlarged view of FIG. 95(B) andincludes light source 2514 such as for example light emitting diodes oroptic fibers in apposition to the red palpebral conjunctiva 2512 toradiate the conjunctiva/plasma interface 2310 and detectors 2516positioned on the opposite external surface of the eyelid 2410 inapposition with the eyelid skin 2518. Detectors 2516 collect theresulting transmitted radiation which was directed through the eyelid2410.

[1135] Eyelid 2410 is an ideal alternative for measurement since saideyelid 2410 is highly vascularized and one surface 2512 is transparentwith plasma 2330 present while the opposing surface 2518 is comprised ofa unique type of skin. Although there is interaction of the radiationwith skin, which as described can be an important source of errors, theskin of the eyelid is uniquely fit for measurements because of itscharacteristics.

[1136] The skin 2518 covering the lower eyelid 2410 is the thinnest skinin the whole body. The skin 2518 of the eyelid 2410 is also the onlyskin area in the body which there is no fat layer. Since fat absorbssignificant amounts of radiation over an important portion of theglucose absorbance spectrum, there is a significant reduction of signalwhen the substance of interest 2350 is glucose. This interference by thepresence of a fat layer does not occur in the skin 2518 of the eyelid2410.

[1137] This can be easily observed by pinching the skin of the lowereyelid. One can then easily feel that only a very thin skin is grasped.The same grasping in any other part of the body will show that a muchthicker amount of skin is pinched. Those characteristics, contrary tothe skin in the rest of the body, enable the acquisition of a goodsignal to noise ratio. However, the preferred way of the presentinvention includes complete elimination of the skin as source of errorsand variability.

[1138] The apparatus of this alternative embodiment 2510 can include amanual, spring, or automatic adjustment system for engagement andpositioning of the device at the edge of the eyelid 2410, right abovethe eyelashes 2522. The apparatus can also include a fixed predeterminedspace between source 2514 and detector 2516 according to the individualcharacteristics of the eyelid 2410. Although one means to grasp theeyelid was described, it is understood that a variety of manual orautomatic assemblies to grasp the edge of the eyelid 2410 can be used.In this embodiment, clinical calibration instead of analyticalcalibration can be used and the device 2510 is calibrated according tothe fairly constant skin and tissue characteristics of said eyelid skin2518.

[1139] As shown in FIG. 96, the forceps probe 2520 is grasping thebulbar conjunctiva and plasma interface 2310. The forceps probe 2520 canbe wirelessly connected with the main body housing 2524 via RFtransceiver 2526 in the probe 2520. The forceps probe 2520 can includethe light source 2528 and detector 2530, optic fibers 2532 for directingradiation and optic fibers 2534 for collecting radiation which hasinteracted with the substance of interest 2350 present in the plasma2330. The signal 2536 is wirelessly transmitted to the RF transceiver2538 in the main body housing 2524. The main body 2524 also encases thedisplay 2540, and memory and processor 2542 which makes a spectrumanalysis of the collected resulting radiation and determine theconcentration of the substance of interest 2350. Conventionalstatistical analysis and models can be used for the determination ofconcentration of the substance of interest 2350, but said analysis andmodels are simplified and less prone to errors since the majority ofinterfering constituents are eliminated in accordance with theprinciples of the present invention. The tip of the forceps probe 2520serves to receive the conjunctiva/plasma interface 2310 with thesubstance of interest 2350 to be measured. The position of the forcepsarms are arranged to adjust the proper spacing with respect to theconjunctiva/plasma medium 2310 to remain stable during the measurement.

[1140] A further embodiment as shown in FIGS. 97A and 97B can include aforceps-like system 2560 embedded in a contact device 2562 with two armsextending from the main body of the contact device 2562. A light source2564 and a light detector 2566 are encased in said contact device 2562and located diametrically opposed to each other, preferably at a fixeddistance. In this embodiment the bottom part of the contact device 2562lodges in the cul-de-sac 2404 of the eyelid pocket. The recess presentbetween the two arms 2564 and 2566 in the bottom part of the contactdevice 2562 captures the plasma/conjunctiva interface 2310.

[1141] In this embodiment the output of the forceps-like system 2560 canbe wirelessly communicated to the receiving unit/processor 2568. Theprocessor 2568 is programmed to execute algorithm and functions neededto determine the concentration of the substance of interest 2350. FIG.97(C) shows an alternative embodiment in which the contact device 2570communicates the output by a micro wire 2572 connected to a receiver2572 a and to a processor and display (not shown). Radio transceiver2572 a can include an adhesive patch that is attached to the skin. Themicro wires 2572 can comfortably exit the eye and be connected with theadhesive transceiver 2572 a. The signal can then be transmitted toanother receiver for further processing and display. Alternatively,transceiver 2572 a can be comprised of processing and display means. Abooster or transceiver placed around the ear can also be used to receivethe signal from either contact device 2750 (wired) or 2400 (wireless) onthe eye. Contact device can be used for measurement of temperature aswell as evaluation of the concentration of the substance of interest.

[1142]FIG. 98(A) shows the measuring ICL 2580 in which only the tip ofthe sensor 2574 penetrates the conjunctiva 2320. The tip 2574 is bathedby the plasma 2330 with the substance of interest 2350 in direct contactwith the sensor tip 2574. The tip 2574 can include an electrochemicalsensor, an optical sensor, or the like. In addition, fiberoptic optodescan be used in the tip 2574 to continuously monitor pH, carbon dioxidepartial pressure, and oxygen partial pressure. The main body 2576 of themeasuring ICL 2580 is located in the eyelid pocket 2420 and restsagainst the conjunctiva 2320. The signal 2578 can be wirelesslytransmitted to an external receiver 2580. This embodiment provides acost-effective away of achieving the measuring function since there isno need for the main body 2576 to be in intimate apposition to theconjunctiva for capturing flow of plasma 2330 with the substance ofinterest 2350 in case of using electrochemical techniques.

[1143] The main body 2576 can be made with inexpensive biocompatiblepolymers that do not need to intimately interact with the surface of theconjunctiva 2320. The flow of plasma occurs directly into the sensingmeans of the tip 2574. The tip 2574 of the sensor is placed in intimateand immediate contact to the plasma 2330 flowing from the blood vessels.FIG. 98(B) shows a cross-sectional view of the eye, eyelid 2410, andeyelashes 2522. The measuring ICL 2580 is in the eyelid pocket 2420. Thetip 2574 of the sensor penetrates the conjunctiva 2320 and is bathed byplasma 2330 and substance of interest 2350 in the cul-de-sac area 2404.

[1144]FIG. 99(A) shows an alternative embodiment in which the sensor2582 is housed in an intraocular lens 2590. The measuring intraocularlens 2590 includes a transparent main body 2584 usually with opticalproperties. The measuring intraocular lens 2590 can be used as areplacement for the diseased natural lens of the eye during a cataractoperation, an optical surface placed in addition to the natural lens ofthe eye for correction of refractive errors, and the like. The measuringintraocular lens 2590 is implanted surgically inside the eye. Thisintraocular lens 2590 then is bathed by the aqueous humor 2588 with itsvarious substances of interest 2350.

[1145] Although this alternative embodiment requires a surgicalprocedure and the substance of interest 2350 is present in dilutedquantities, this embodiment allows direct contact of the aqueous humor2588 with the sensor surface 2582. Sensor 2582 can includeelectrochemical sensors, optical sensors, chemical sensors, or the like.The sensor 2582 can be encased in the main body 2584 and acquire thesignal corresponding to the substance of interest 2350 as previouslydescribed.

[1146] The signal is then transmitted to a remote receiver and processor(not shown) for identification and determination of the concentration ofthe substance of interest. The apparatus can include a main body 2584with or without optical properties with the sensor 2582 encased in saidmain body 2584 and the haptics 2586 of the intraocular lens 2590 beingused as antennas. The sensor 2582 can also be attached to one of thehaptics 2586.

[1147]FIG. 99(B) shows a cross section of the eye with the intraocularlens 2590 implanted and placed in the capsular bag. The main body 2584with sensor 2582 is positioned in the center with the haptics 2586providing a supporting function. The substance of interest 2350 presentin the eye fluid 2588 interacts with the surface of the sensor 2582.

[1148]FIG. 99(C) shows an alternative embodiment with modified main body2592 and haptics 2586. This modified main body 2592 houses in itsperiphery light source 2594 and light collectors 2596 diametricallyopposed to each other. The substance of interest 2350 is present in thefluid 2588 that bathes the lens 2600 and the recess 2598 formed betweenlight source 2594 and collector 2596. In this embodiment the sensorsystem can be powered using active or passive means includingelectromagnetic coupling, photoelectric cell using energy from theenvironment, biological sources, and the like.

[1149] Alternatively as shown in FIG. 99(D), an intra-vitreal implantplate 2610 can be used. The sensor 2612, includes optical,electrochemical sensors or the like. The sensor 2612 can be placed inthe vitreous cavity 2614 inside the eye using an incision around thepars plana 2616 area of the eye which is the area between the ciliarybody 2618 and the retina 2620. In this embodiment the sensor 2612 isencased in a biocompatible plate 2610 and inserted inside the eye in thevitreous cavity 2614. The plate 2610 is secured with a stitch to thesclera and the sensor 2612 is in contact with the vitreous humor of theeye.

[1150] Besides reflectance and transmission spectroscopy, the methodsand apparatus of the present invention provide optimal detection usingother regions of the electromagnetic spectrum. Another preferredembodiment includes measurement of substances in eye fluid and plasmausing far-infrared spectroscopy and will be described in detail below.For example but not by way of limitation two other techniques that canuse other regions in the electromagnetic spectrum will be brieflydescribed: radio wave impedance and fluorescent techniques.

[1151] Now with reference to FIG. 100(A), the temperature andfar-infrared detection ICL 2650 includes a housing 2652 having the shapeof a contact device to engage the surface of the eye and an infraredsensor 2654 which detects infrared radiation from the eye. Thefar-infrared detection ICL 2650 is preferably placed in the eyelidpocket 2420 which allows intimate and stable contact with the tissue inthe eye.

[1152] Referring to FIG. 100(B), an infrared sensor 2654 is placed inapposition to the conjunctiva 2656 bulbar or palpebral, but preferablythe bulbar conjunctiva in apposition to the sclera. Alternatively theface of the sensor 2654 can be placed in apposition to the red palpebralconjunctiva 2656, with said conjunctiva containing blood vesselssuperficially and being in apposition to the eyelid. The heat radiation2660 emitted by the plasma 2658 in apposition to the sclera 2659 travelsdirectly to the infrared sensor 2654. The heat radiation 2660 passesonly through the thin conjunctiva 2656 with said infrared emission 2660not being absorbed by the conjunctiva 2656.

[1153] The infrared emission 2660 from the blood/plasma 2658 in theconjunctival vessels is collected by the sensor 2654 which can includean infrared sensor or other conventional means to detect temperature oncontact. The temperature sensor 2654, preferably a contact thermosensor,is positioned in the sealed environment provided by the eyelid pocket2420, which eliminates spurious readings which can occur by accidentalreading of ambient temperature. The sensor 2654 can measure theintensity of the infrared radiation 2660.

[1154] For example, a thermopile sensor which converts the infraredradiation 2660 into an electrical signal can be used or a temperaturesensor as a thermistor-like element. The sensor 2654 coupled with afilter that correlates with the substance of interest converts saidinfrared energy 2660 into an electrical signal. The signal is thentransmitted by wireless or wired transmission to a processor (not shown)which calculates the concentration of the substance of interest.

[1155]FIG. 100(C) shows a schematic block diagram of one preferredfar-infrared spectroscopy measuring apparatus of the present invention.The apparatus includes a thermal infrared detector 2654 which has afilter 2662 and a sensing element 2664 with said sensing element 2664being preferably a thermopile and responding to thermal infraredradiation 2660 naturally emitted by the eye. A variety of infraredsensors responsive to thermal radiation can be used as sensor 2664besides a thermopile, such as for example, optoelectronic sensorsincluding thermistor-based infrared sensor, temperature sensitiveresistor, pyroelectric sensors, and the like, and preferably thinmembrane sensors. The detector 2654 faces the conjunctiva 2656 and ifthe face of the detector 2654 is encased by the housing 2652 material,said material is preferably transparent to infrared radiation.

[1156] The far-infrared radiation 2660 emitted by the conjunctivalblood/plasma 2658 (within the spectrum corresponding to thermalradiation from the body; from 4,000 to 14,000 nm) is partially absorbedby the substance of interest 2350 according to its band of spectralabsorption and which is related in a linear fashion to the concentrationof said substance of interest 2350. For example in the thermally sealedand thermally stable environment in the eyelid pocket 2420 (FIG. 102A),at 38 degrees Celsius spectral radiation 2660 emitted as heat by the eyein the 9,400 m band is absorbed by glucose in a linear fashion accordingto the amount of the concentration of glucose. The resulting radiationfrom conjunctiva/plasma 2658 is the thermal emission 2660 minus theabsorbed radiation by the substance of interest 2350.

[1157] This resulting radiation enters the infrared detector 2654 whichgenerates an electrical signal corresponding to the spectralcharacteristic and intensity of said resulting radiation. The resultingradiation is then converted into digital information by converter 2666.The signal 2671 is then transmitted by RF transceiver 2668 to a remotelyplaced receiver 2670 connected to a processor 2672.

[1158] The processor 2672 then calculates the concentration of thesubstance of interest 2350 according to the amount of thermal energyabsorbed in relation to the reference intensity absorption outside thesubstance of interest band. The output can be adapted to report thevalue on a display 2674, activate an audio transmitter 2676, and controldispensing means 2678 for the delivery of medications.

[1159] A variety of filters can be used to include the spectral regionof correlation to the substance of interest. The apparatus can alsoinclude a heating induction element and cooling element as well as lightradiation and collection means (not shown) to create an integratedfar-infrared and near-infrared system. The front surface of contactdevice can have a coating to increase energy transfer in the spectralregion of interest.

[1160] In reference to FIG. 100(D), the temperature and far-infrareddetection ICL 2651 includes a housing 2653 having the shape of a contactdevice to engage the surface of the eye and a dual infrared detectorarrangement 2654 which is selected to detect far-infrared radiationcorresponding to the substance of interest, and sensor 2655 which isused as a reference and detects radiation outside the wavelengthcorresponding to the substance of interest. Filters are used to select awavelength of interest and a reference wavelength to calculate theconcentration of the substance of interest. The far-infrared detectionICL 2651 is preferably placed in the eyelid pocket 2420 which allowsintimate and stable contact with the tissue and source of heat as foundin the eye surface.

[1161] A contact device with a germanium coated selective filter coupledto a thermopile detector was constructed and used to non-invasivelymeasure conjunctival plasma glucose emitted as thermal emission from theeye. The preferred embodiment comprised an arrangement which includedthe thermopile coupled to the germanium coated selective filter forpassing a wavelength corresponding to a wavelength of high correlationwith the substance of interest.

[1162] For this exemplary measurement of glucose, wavelength centeredaround 9,400 nm (glucose band) was used. There is a prominent absorptionpeak of glucose around 9,400 nm due to the carbon-oxygen-carbon bond inits pyrane ring present in the glucose molecule. The contact devicefilter system allowed passage of the glucose band which is used as areference measuring point while simultaneously measuring thermal energyabsorption outside the glucose band. The thermal energy absorption inthe glucose band by plasma glucose is spectroscopically determined bycomparing the measured and predicted radiation at the conjunctivalsurface.

[1163] The predicted amount of thermal energy radiated can be calculatedby the Planck distribution function. The absorption of the thermalenergy in the plasma glucose band is related in a linear fashion toglucose concentration and the percentage of thermal energy absorption isarithmetically converted to plasma glucose concentration. One preferredembodiment includes a dual detector arrangement in the same contactdevice. One detector has a filter for reference and the other has anarrow band pass filter for the substance of interest. The ratio of thetwo wavelengths is used to determine the concentration of the substanceof interest.

[1164] The system and method of the invention using theconjunctiva/plasma interface solves all of the critical problems withthe technique of using thermal emissions by the body for non-invasiveanalysis. One of the critical issues is related to the fact that thesignal size of human thermal emissions is very small as occurs in theskin, mucosal areas, tympanic membrane and other surface areas in thebody. This inability of acquiring a useful signal is in addition to theother drawbacks and interfering constituents previously mentioned. Thepresent invention using its preferred embodiments achieves a high signaland correlation by providing a unique place in the body that combines athermally sealed and stable environment as in the eyelid pocket with acontact device that provides direct contact of detector to the source ofheat (blood and plasma) associated with measurement of core temperature,large area of the contact sensor to detector, no interferingconstituents, and with active heat transfer from the tissue to thedetector.

[1165] In addition, due to the characteristics of the conjunctivalplasma interface as described and high signal obtained, other noveltechniques can be easily achieved. One of them includes the use of acalibration line as another preferred embodiment. The concentration ofplasma glucose can be obtained by invasive means and analyzed in thelaboratory setting. The range of glucose levels of usual interest inclinical practice (40 to 400 mg/dl) obtained invasively creates areference database to be correlated to the intensity of radiationobtained using the contact device in the eyelid pocket of the presentinvention. Planck's function can be used to convert temperature tointensities. This invasive reference is done for each clinically usefullevel of temperature, for example 35 to 41 degrees Celsius. For example,at 37 degrees Celsius, the concentration of glucose (e.g. 100 mg/dl wasthe glucose level) measured invasively correlated to the spectralintensity value detected at 9,400 nm by the contact device. Theconcentration of the substance of interest is then determined bycorrelating the predicted value with the acquired (unknown) value usingthe predetermined calibration line.

[1166] Alternatively, a temperature sensor can be included in thecontact device and provide a correction factor according to the level oftemperature thus avoiding a calibration table that requires differentlevels of reference temperature. Processing applies automatically thereal time value of the temperature to determine the concentration of thesubstance of interest. Yet in another alternative embodiment, inputmeans can be provided that allows the user to input the temperaturevalue manually with processing applying that value when calculating theconcentration.

[1167] Alternatively, a heating element is incorporated in the contactdevice. The increase in temperature creates a reference measurementwhich is correlated with the measurement achieved using the naturalthermal emission. Moreover, a bandpass filter can be used to select oneparticular wavelength such as 11,000 nm that is used as a reference andcompared to the wavelength of the substance of interest creating a dualdetector system with narrow bandpass interference filter. Onedetector/filter passing a narrow range of radiation centered at 9400 nmand a second detector/filter passing radiation centered at 11000 nm.Selective filters are used to adjust passage of radiation related to thespectrum region of interest, in the case of glucose from 9,000 to 11,000nm. For detection of ethanol levels the 3,200 to 3,400 nm region of thespectrum is selected. Alternatively, a heating and cooling of thesurface of the conjunctiva can be used and the thermal gradient used todetermine the concentration of the substance of interest.

[1168] Another preferred embodiment includes the use of Beer-Lambert'slaw in-vivo to determine the concentration of the substance of interestusing thermal emissions. In other parts of the body, with the exceptionof the eyelid pocket and surface of the eye, various natural phenomenaand structural characteristics occur that prevent the direct in-vivo useof Beer's law for the determination of the concentration of thesubstance of interest:

[1169] 1. The optical path length cannot be determined. In standardspectroscopic calibration and in-vitro measurement, the optical pathlength comprises the length traversed by light in the sample beingevaluated such as for example contained in a cuvette. In any part of thebody the thermal emission travels an unknown path from the origin ofheat deep in the body until it reaches the surface.

[1170] 2. Self-absorption. This relates to the phenomena that deeplayers of tissue selectively absorb wavelengths of infrared energy priorto emission at the surface. The amount and type of infrared energyself-absorbed is unknown. At the surface those preferred emissions areweak due to self-absorption by the other layers deriving insignificantspectral characteristic of the substance being analyzed. Self-absorptionby the body thus naturally prevents useful thermal emission formeasurement to be delivered at the surface.

[1171] 3. Thermal gradient. The deeper layers inside the body are warmerthan the superficial layers. The path length increases as the thermalgradient is produced. This third factor in addition to the two describedabove to further prevent undisturbed natural body heat to be used fordetermination of concentration of substances. Moreover, there isexcessive and highly variable scattering of photons when passing throughvarious layers such in the skin and other solid organs. This scatteringvoids the Beer-Lambert law due to radiation that is lost and notaccounted for in the measurement associated to an unknown extension ofthe optical path length and other thermal loss.

[1172] The characteristics of the conjunctiva/plasma interface asdescribed fits with and obeys Beer-Lambert's law. The conjunctiva is atransparent surface covering a clear solution (plasma is clear whichprevents multiple scattering) which contain a substance to be measuredsuch as glucose. Due to the unique geometry of the conjunctiva/plasmainterface, the method and apparatus of this preferred embodiment providefor a key variable in-vivo that allows direct use of Beer-Lambert's law,which is the optical path length. The embodiment provides the equivalentof an in-vivo “cuvette” since the conjunctiva/plasma interface thickness(d) is stable for each location in the eye. The mid to inferior third ofthe undisturbed bulbar conjunctiva/plasma interface measures 100 μm.Dimensions (d) are similar for each area but can vary greatly from areato area reaching a few millimeters in the lower parts and 20 micrometersin the upper third of the conjunctiva/plasma interface.

[1173] One face of the cuvette is the conjunctiva surface and the otherface is the sclera with clear plasma in between. The sclera has tissueinsulation characteristics that make this surface of the cuvette as theorigin of the thermal radiation. The sclera accomplish that because itis a tissue completely avascular, white and cold in relation to theconjunctiva/plasma interface which has the heat source coming from theblood and plasma. The efficiency with which glucose absorbs light iscalled extinction coefficient (E). E is measured as the amount ofabsorption produced over 1 cm optical path length by 1 molar solution.Then, the radiation absorbed or Absorbance (A=log I_(o)/I) by thedissolved material (e.g., glucose) equals the molar extinctioncoefficient (E) of the substance of interest for the particularwavelength employed times the concentration (c) times the optical pathlength (d). The equation can be written as:

A=log(I _(o) /I)=E·c·d  (1)

[1174] And rewritten to determine the unknown concentration (c)

c=A/E·d  (2)

[1175] where Io can be measured as the original intensity of theincident radiation, I is the transmitted intensity through the samplecorresponding to the substance of interest according to the wavelengthselected and can be detected with a photodetector.

[1176] The other two interfering problems above, self-absorption andthermal gradient, are also eliminated providing the accuracy andprecision needed for clinical application. There is no self-absorptionby tissues. The radiation (heat) is generated by the local blood/plasmaflow and the only tissue traversed is the conjunctival lining which doesnot absorb the radiation. There is no other tissue interposed in thepath from source (heat in the eye surface) to detector. In addition,there are no deep or superficial layers interposed and since the sourceof heat (blood/plasma) is in direct apposition to the detector, thermalgradient is insignificant.

[1177] Filters can limit the wavelength (thermal radiation) to thedesired range. It is understood that multiple filters with differentwavelength selectivity can be used for the simultaneous measurement ofvarious substances of interest. For example a selective filter allowspassage of 9,400 nm band when the substance of interest is glucose. Theincident thermal energy traversing the detector, for example athermopile detector, is proportional to the glucose concentrationaccording to a calibration reference. Alternatively filters can be usedto select a wavelength of interest and a reference wavelength tocalculate the concentration of the substance of interest as previouslydescribed. Yet alternatively the ratio of the concentration of water tothe substance of interest can be used to determine the concentrationsince the concentration of water is known (molecular weight of water is18 forming a 55.6 molar solution with water band at 11000 nm).

[1178] The same principles disclosed above can be used for near-infraredtransmission measurements as well as for continuous wave tissueoximeters, evaluation of hematocrit and other blood components. Thesubstance of interest can be endogenous such as glucose or exogenoussuch as drugs including photosensitizing drugs.

[1179] Photosensitizing agents are a class of drugs used in PhotoDynamicTherapy (PDT). PDT relies on photoactivation of an exogenouslyadministered photosensitizing drug. A variety of cancers and age-relatedmacular degeneration can be treated in this fashion. Those drugs areinjected in the circulation of a patient and activated by light afterreaching the target organ. The time point between the injection of thephotosensitizing drug and exposure to light is critical. However,previously there was no way to determine the time according to real-timemeasurement of the concentration of the drug in the patient.

[1180] For example, in the treatment of macular degeneration in the eye,an arbitrary time of 15 minutes from the time of injection to applyinglight is chosen for all patients using verteporfin. This time relates toan attempt to achieve optimal concentration of the drug in the targettissue and presumes that all patients will have the same amount of thedrug in the eye after 15 minutes. However, substantial variation inpharmacodynamics and pharmacokinetics of the drug can occur from patientto patient preventing an optimum time from injection to photoactivationto be achieved without actually measuring the concentration of the drugin plasma. If photoactivation is done too early it can damage thetissue, and if done too late has no therapeutic effect.

[1181] By knowing the concentration of the drug an optimum time forphotoactivation can be achieved in addition to adjusting the amount ofenergy delivered in accordance to the concentration of the drug. In thecase of the eye, an accurate concentration of the drug in the retina canbe achieved by measuring the concentration of the drug in theconjunctiva. In addition, measurement of drug concentration in plasmapresent in the eye accurately reflects the concentration of the drug inother parts of the body.

[1182] The concentration of the drug can be determined in various ways.In the case of the eye using the drug verteporfin, photoactivation isachieved using a wavelength of 689 nm. A light source providing the samewavelength (689 nm) could be used but has the risk of photoactivationand damage of tissue. It is preferably then that an infrared LED ofshorter wavelength, for example an AlInGaP LED, can be used to deliverradiation that interacts with the drug present in the conjunctivalplasma.

[1183] The intensity of the reflected radiation is measured byphotodetectors adjusted to receive the peak absorption radiation fromthe drug present in the conjunctival plasma. Determination of theconcentration of the drug can be done by directly applyingBeer-Lambert's law as described or comparing the measured value againsta predetermined calibration line. The calibration consists of therelationship between the physical quantity measured to the signalobtained.

[1184] Other exemplary agents include purlytin (tin ehtyl etiopupurin)which is photoactivated at 664 nm. A determination of concentrationachieved can be obtained in a similar manner as described forverteporfin.

[1185] Yet another exemplary agent includes lutetium texaphyrin. In thiscase photoactivation is achieved using a wavelength of 732 nm. In thiscase a light source in the contact device, such as a LED, illuminatesthe conjunctiva at a wavelength of 690 nm. When illuminated at 690 nmthe lutetium texaphyrin fluoresces at 750 nm. A suitable detector for750 nm is incorporated to detect the intensity of the reflectedradiation which can be done with the detector being in direct contactwith the tissue ors by non-contact means with an externally placeddetector aimed at the conjunctiva.

[1186] The apparatus which is employed for single or continuousmeasurement of temperature, but not for determining concentration of thesubstance of interest can include a simpler arrangement than. theembodiment for determination of the concentration of the substance ofinterest. In accordance with this exemplary embodiment for temperaturemeasurement as shown in FIG. 101(A), the thermal energy 2682 emitted bythe eye is sensed by the temperature sensor 2680 such as a miniaturethermistor which produces a signal representing the thermal energy 2682sensed. The signal is then transmitted by RF transmitter 2685 to aremotely placed receiver 2687. The signal is then converted to digitalinformation by A/D converter 2684 and processed by processor 2686 usingstandard processing for determining the temperature. The temperaturelevel can then be displayed in degrees Centigrade, Fahrenheit or Kelvinin display 2688.

[1187] The processor 2686 can also control activation of ICL system 2690for detection of infectious agents during a temperature spike. If aninfectious agent is identified as by microfluidic systems, the processor2686 can control the delivery of antibiotics according to the infectiousagent identified, or control chemotherapy if cancer markers areidentified. Drug dispensing devices implanted in the eye (inside theglobe or under the conjunctiva) can be used to deliver drugs accordingto the signal received.

[1188] The tear punctum area and inner canthal area of the eye areimportant for measuring substances non-invasively and for themeasurement of core temperature. The punctum and inner canthal area isthe hottest part of the body that is exposed (not in the eyelid pocket)to the environment and that reflects core temperature. A temperaturesensor can be placed against the inner canthal area and tear punctumwith the remaining RF transmitter and electronics placed inside theeyelid pocket.

[1189]FIG. 101(B) shows a cross-sectional view of the eye with atemperature measuring contact device 2681. The contact devicethermometer includes two miniature temperature sensors 2683, 2689, forexample a passive temperature sensor such as a thermocouple. Sensor 2689is in apposition to the cornea facing the ambient and measuring corneatemperature. Sensor 2683 is inside the eyelid pocket and measuring coretemperature. The signal from both sensors 2683, 2689 is transmitted toan external receiver 2687.

[1190] This embodiment can be used for measurement of temperature andthe differential used to evaluate the presence of disorders such ascancer which increases temperature. Although two temperature sensors areshown it is understood that only one temperature sensor on the corneacan also be used as well as multiple temperature sensors encased in anypart of the contact device disclosed.

[1191] A variety of temperature sensing elements can be used as atemperature sensor including a thermistor, NTC thermistor, thermocouple,or RTD (Resistance Temperature Detector). A temperature sensing elementconsisting of platinum wire or any temperature transducer includingtemperature sensitive resistors fabricated from semiconductor materialare also suitable. Other sensing means that can change value over timeand provide continuous measurement of temperature include:semiconductors, thermoelectric systems which measure surfacetemperature, temperature sensitive resistors in which the electricalresistance varies in accordance with the temperature, and the like.Those temperature sensors and resistance temperature device can beactivated by closing or blinking of the eye.

[1192] Alternatively, a low mass black body coupled to an optic fiberwhich fluoresces according to the temperature can be used. The amount oflight is proportional to the temperature. An alternative embodimentincludes reversible temperature indicators including liquid crystalMYLAR sheets. External color detectors read the change in color whichcorresponds to the temperature.

[1193]FIG. 102(A) shows the far-infrared detection Intelligent ContactLens 2650 in the eyelid pocket 2420 which provides non-invasivemeasurement of the substance of interest using natural eye emission asheat in addition to providing measurement of core temperature of thebody. The sensor 2654, in contact with the conjunctiva 2656 andsubstance of interest 2350, draws thermal energy (heat) from saidconjunctiva/plasma 2658 and maximizes the temperature detectionfunction. There is no interference since the heat source which is theblood/plasma flow in the surface of the conjunctiva 2656 is in directapposition to the sensor 2654. The eyelid pocket 2420 functions as acavity since the eyelid edge 2693 is tightly opposed to the surface ofthe eyeball 2692. The eyelid pocket 2420 provides a sealed andhomogeneous thermal environment. There is active heat transfer from theconjunctiva/plasma 2658 to the sensor 2654 caused by local blood/plasmaflow which is in direct contact with said sensor 2654. The opposingsurface, the sclera 2659, serves as an insulating element. Theincreasing surface-to-surface contact as occur naturally in the eyelidpocket 2420 (conjunctiva surface-to-sensor surface contact) increasesthe rate of heat energy 2660 transfer from conjunctiva 2656 totemperature sensor 2654.

[1194]FIG. 102(B) shows the far-infrared detection Intelligent ContactLens 2651 in the eyelid pocket 2420 which provides non-invasivemeasurement of the substance of interest using natural eye emission asheat in addition to providing measurement of core temperature of thebody. The sensor 2654 in contact with the red palpebral conjunctiva 2657and substance of interest 2350 draws energy from said conjunctiva 2657and blood vessels 2661 to maximize temperature detection function. Theheat source which is the blood/plasma flow in the surface of theconjunctiva 2657 is in direct apposition to the sensor 2654. The eyelidpocket 2420 functions as a cavity since the eyelid edge 2693 is tightlyopposed to the surface of the eyeball 2692.

[1195] The eyelid pocket 2420 provides a sealed and homogeneous thermalenvironment with capillary level 2661 present in the surface. There isactive heat transfer from the vessels 2661 to the sensor 2654 caused bylocal blood/plasma flow which is in direct contact with said sensor2654. The increasing surface-to-surface contact as occur naturally inthe eyelid pocket 2420 (conjunctiva surface-to-sensor surface contact)increases the rate of heat energy 2660 transfer from conjunctiva 2657 totemperature sensor 2654.

[1196]FIG. 102(C) shows an alternative embodiment illustrating across-section view of the eye with cornea 2694, upper and lower eyelids2410, 2411, anterior segment of the eye 2696 with aqueous humor 2588 andsubstance of interest 2350 in said anterior chamber 2696 of the eye.FIG. 102(C) also shows the eyes closed with the thermal sensor 2654located on the surface of the cornea 2694 and the substance of interest2350 and thermal emission 2660 coming through the cornea 2694. When theeyelids are closed (during blinking or during sleeping), the thermalenvironment of the eye is exclusively internal corresponding to the coretemperature of the body. This alternative embodiment can be preferablyused for measurement of temperature or substance of interest 2350 duringsleeping.

[1197] Radio wave impedance techniques can also be used and enhanced bythe principles of the invention. Impedance is proportional to thedifferences in amplitude and phase of the wave compared to a referencewave. Radio waves promote excitation of molecular rotation. In referenceto FIG. 103, the substance of interest 2350 interacts with the radiowave 2700 to attenuate the amplitude and shift the phase of the wavecreating a resulting wave 2702. The resulting impedance 2702 isproportional to the concentration of the substance of interest 2350which can be calculated using a conversion factor.

[1198]FIG. 103 shows the substance of interest, for example a nonionicsolute such as glucose, which interacts with a radio wave 2700 that ispassed through the conjunctiva/plasma interface 2310. Since there arefew interfering elements and glucose in plasma is in relative higherconcentration compared to background, the concentration can beaccurately and precisely obtained.

[1199] Light induced fluorescence can be used since the since the plasmawith the analyte to be measured is present on the surface. A variety offluorescent techniques can also be used to identify or quantify asubstance or cellular constituent. A variety of disorders includingbacterial infection, degenerative diseases such as Alzheimer, multiplesclerosis and the like can be identified by for example emitted light orfluorescent light generated by interaction with degenerated constituents(not shown). The radiation induced fluorescence depends on thebiochemical and histomorphological characteristics of the sampleincluding presence of cancerous cells which can be opticallycharacterized in the surface of the eye and conjunctiva.

[1200]FIG. 104(A) shows a probe arrangement for reflectance measurementwith a wired handle 2730 which contains the fiber optic bundles fordelivery of and collection of radiation directed at the substance ofinterest 2350 present in the conjunctiva/plasma interface 2310. Theprobe can also work as a pen like device with the signal beingwirelessly transmitted to an external receiver.

[1201]FIG. 104(B) shows a schematic illustration of another preferredembodiment using non-contact infrared detection of thermal radiationfrom the conjunctiva/plasma interface 2310. A penlight 2731 measuringdevice receives radiation 2660 which passes through filter 2733corresponding to high correlation with the substance of interest 2350and filter 2732 that works as a reference filter outside of the rangecorresponding to the substance of interest 2350. The pen 2731 containsthe electronics and processing (not shown) needed to calculate anddisplay the data. Display 2737 shows the concentration of the-substanceof interest, for example the glucose value and display 2735 shows thetemperature value. FIG. 104(B1-B3) shows illustratively the differentlocations in the eye that measurement can be done, in the conjunctiva2739, in the inner canthal area and tear punctum 2741, and in the cornea2742.

[1202]FIG. 104(C) is a block diagram of a continuous measurement systemof the invention in which the infrared detector is mounted preferably inthe frame of eye glasses. A head-band and the like can also be used. Thefield of view of the infrared sensor is directed at the exposedconjunctival area when the eyes are open. The continuous signal of theinfrared sensor is delivered to a RF transmitter which transmits thesignal to an external receiver for subsequent-processing and display.

[1203]FIG. 104(D) shows the measuring pen 2731 coupled with a telescopeor lighting system which are in line with the area from which radiationis being emitted from the surface of the eye. This allows precise aimand indicates the area being measured for consistency.

[1204]FIG. 104(E) is a schematic view of the probe of pen 2731. The tiprests against the conjunctiva 2320 with a sensor arrangement located ina recess inside the tip of the probe. The sensor arrangement includesfilter 2662 a for the substance of interest and 2662 b that is used as areference and infrared detector 2664.

[1205] FIGS. 104(F-G) show a cross-sectional view for various positionsof the probe of pen 2731 in relation to the conjunctiva. FIG. 104(F)show the probe resting on the conjunctiva 2320 and covered by disposablecover 2665 while FIG. 104(G) shows the probe receiving thermal radiation2660 away from the conjunctiva 2320.

[1206] FIGS. 104 (H-J) show in more detail some arrangements forselecting substance of interest according to the wavelength. FIG. 104(I)shows filter 2662 a corresponding to the substance of interest andfilter 2662 b used as a reference. FIG. 104(J) shows a similararrangement as in FIG. 104(I) with an additional temperature sensor2667. FIG. 104(H) shows a preferred embodiment with a selectionarrangement consisting of infrared sensor 2662 e receiving thermalradiation 2660 from conjunctiva 2320 at the body temperature. Infaredsensor 2662 e has two junctions, a cold junction 2662 d and a hotjunction 2662 c. The cold junction is covered with a membrane (notshown) to reduce the amount of heat reaching said cold junction 2662 d.In addition, the cold junction 2662 d is artificially cooled and thusreceives the radiation from the conjunctiva 2320 at a lower temperature.The increased temperature gradient created increases the voltage signalof detector 2662 e facilitating determination of the concentration ofthe substance of interest. Alternatively, the cold junction 2662 d ismounted surrounding the hot junction 2662 c (not shown) and an apertureis created to direct the heat toward the hot junction 2662 c whileavoiding the cold junction 2662 d. The above arrangements which increasethe temperature gradient in the infrared sensor helps said sensor 2662 eto remain with a high signal since when the narrow band pass filter isplaced in front of the infrared detector the signal is decreased. Narrowband pass filters such as found in rotatable filter 2673 are placedpreferably in front of the hot junction and centered at the wavelengthcorresponding to the substance of interest. The signal can also beincreased by increasing the number of junctions in the detector andincreasing the resistance. A thermistor can be incorporated to measurethe temperature in the cold junction in order to accurately measure thetemperature of the conjunctiva. The probe head 2731 a of pen 2731 caninclude a wall (not shown) positioned between sensor 2662 c and sensor2662 d similar to the one described in FIG. 86.

[1207] A variety of means can be used to increase the temperaturegradient between the hot and cold junctions of a thermopile and increasethe signal including using a power source to bring the cold junction toa lower temperature. Besides using thermoelectric means, contact coolingwith cold crystals or cold bodies can be used to decrease thetemperature of the sensor. When using the contact device 2400 thecooling of the cold junction cools the conjunctiva in a very efficientmanner since the conjunctiva is very thin and has a small thermal mass.When using the pen 2731 the cooling of the infrared sensor is carriedfrom the surface of the sensor to the conjunctival surface with coolingof said conjunctival surface.

[1208] Due to the characteristics of the conjunctiva/plasma interface asdescribed, with direct application of Beer-Lambert's law anddetermination of a precise calibration line, a reference filter may beeliminated. This simple and cost-effective arrangement is only possiblein a place like the conjunctiva/plasma interface. The intensity of thereceived radiation is evaluated against a predetermined calibration lineand corrected according to the temperature detected.

[1209] The characteristics of the plasma-conjunctiva interface allows avariety of hardware arrangements and techniques to be used in order todetermine the concentration of the substance of interest as has beendescribed. One preferred embodiment is shown as a cross-sectional viewin FIGS. 104(K-1). The arrangement of probe head of pen 2731 includes arotatable filter 2763 for measurement of various substances according toselection of the appropriate filter corresponding to the substance ofinterest. FIG. 104 (K-2) shows a planar view of rotatable filter 2673including three narrow bandpass filters. The rotatable filter 2763contains filters 2663,2669,2671 corresponding to the wavelength of threedifferent substances.

[1210] For example filter 2663 is centered at 9400 nm for measuringglucose, filter 2669 is centered at 8300 nm for measuring cholesteroland filter 2671 is centered at 9900 run for measuring ethanol. Filter2667 is centered at between 10.5 m and 11 m and is used as a referencefilter. The filter being used is in apposition with detector 2664. Thefilters not being used, for example filter 2663 rests against a solidpart 2773 of the probe not permeable to infrared radiation. Althoughonly one reference filter is shown it is understood that a similarrotatable system with different reference filters can be used accordingto the substance being measured. Infrared detector 2664 can consist ofpassive detectors such as thermopile detectors. The electrical signalgenerated by detector 2664 is fed into the processor (not shown) fordetermination of the concentration of the substance of interest. Avariety of focusing lens and collimating means known in the artincluding polyethylene lens or calcium fluoride lens can be used forbetter focusing radiation into infrared detector 2664.

[1211] By applying Beer-Lambert's law, the ratio of the reference andmeasured values is used to calculate the concentration of the substanceof interest independent of the temperature value. One preferred methodfor determining the concentration of the substance of interest is todirect the field of view of the detector to capture radiation comingfrom the medial canthal area of the eye (corner of the eye), which isthe hottest spot on the surface of the human body. The field of view ofan infrared detector can also be directed at the eyelid pocket liningafter the eyelid is pulled away.

[1212]FIG. 104(L) shows another preferred temperature measuring system2675 in which the temperature detector 2677 rests against the canthalarea (inner corner of the eye) and tear duct of the eye and the body2679 of the contact device rests in the eyelid pocket. FIG. 104(M) showsan alternative embodiment for measurement of concentration of substancesusing far infrared thermal emission from the eye and a temperaturegradient. The contact device 2703 includes infrared sensor 2704.Infrared sensor 2704 has a superior half 2704 a exposed to ambienttemperature above the eyelid pocket and the inferior half 2704 b remainsinside the eyelid pocket measuring core temperature. Alternatively, onesensor can be placed against the skin and another one in the eyelidpocket.

[1213]FIG. 104(N) shows a device 2705 for measuring substances ofinterest or temperature using a band or ring-like arrangement includingboth the upper and lower eyelid pockets.

[1214]FIG. 104(O) shows the pen 2706 connected to an arm 2707 at a fixeddistance. The tip of the pen or probe 2706 has an angled tip to fit withthe curvature of the sclera with a radius of approximately 11.5 mm. Thefiled of view of the pen 2706 is in accordance with the distance of theeye surface to the sensor. The arm 2707 can be used to push the lowerlid down and expose the conjunctival area to be measured. Thisfacilitates exposing the conjunctiva and provides measurement of thesame location and same distance. Fresnell lenses can be added to measuretemperature at a longer distances. An articulated arm or flexible shaftcan also be used to facilitate reaching the area of interest.

[1215] Other alternative means to determine the concentration of thesubstance of interest using the conjunctiva/plasma interface includesusing an actual reference cell with a known amount of the substancebeing measured incorporated in the pen 2731 which is used as areference. In addition, stimulating an enzymatic reaction to processglucose can be used. Since processing of glucose can cause an exothermicreaction, the amount of heat generated can be correlated with the amountof glucose.

[1216]FIG. 104(P) shows simultaneous measurement of temperature of theright and left eye with a non-contact infrared system 2693. Arm 2695carries a sensor measuring temperature for the right eye which isdisplayed on display 2701. Arm 2697 carries a sensor measuringtemperature for the left eye which is displayed on display 2669. Thedifference in temperature (left eye is 101° F. and right eye 97° F.) canbe indicative of a disorder. An asymmetric eye temperature also cancorresponds with carotid disease and nervous system abnormalities.Although temperature was used as an illustration, the device can also beused for detecting asymmetry in the concentration of chemicalsubstances.

[1217]FIG. 104(Q1-Q4) shows a series of photographs for evaluation andmeasurement of thermal radiation from the eye and conjunctiva/plasmainterface. The images were acquired using a computerized high-resolutioninfrared imaging system which measures the far-infrared energy emittedby the eye and displays the images. In the photographs, the amount ofthermal energy goes from highest to intermediate and lowest. In theblack and white images the white digital points correspond to the areasof highest thermal energy, black indicates the coolest part and grayintermediate. The hottest external point in the human body is located inthe inner canthal area. This area corresponds to an exposed conjunctivaand reflects the thermal energy in the eyelid pocket. This is easilyobserved by looking at the eye and noticing the red area in the eye bythe nose which is continuous with the lining in the eyelid pocket.

[1218]FIG. 104(Q1A) shows an image of the thermal energy present in theeye before applying a fan and cold immersion of hands FIG. 104Q1B showsthe image after applying a fan/immersion of hands in cold in order totry to cool down the conjunctiva/plasma interface Note that there isvirtually no change in the amount of thermal energy demonstrating thestability of the thermal emission of the area.

[1219]FIG. 104(Q2A-B) shows black and white images with the hottestpoint appearing as white dots. FIG. 104(Q2A) shows the thermal emissionfrom the red superficial conjunctiva/plasma interface located by thenose with the eyes closed. FIG. 104(Q2B) shows the enormous amount ofthermal energy present in the conjunctival area and margin of the eyelidpocket (B) with the eyes open. Note that the points are of same colorand characteristics indicating same thermal energy present on thesessurfaces. Note that the cornea (A) is cold (dark color) in relation tothe conjunctiva (bright white points).

[1220]FIG. 104 (Q3) shows the symmetry of thermal energy between the twoeyes and the hottest spot located in the canthal area. Note that theremaining portion of the face is cold in relation to the conjunctiva.There are no bright white points on the face with the exception of theinner canthal area.

[1221]FIG. 104 (Q4) shows a close-up view of the lower eyelid beingpulled down by the finger. This maneuver exposes the eyelid pocketlining and conjunctiva/plasma interface showing the high amount ofthermal energy present in the area. Note the great concentration ofbright white points in the surface of the eyelid pocket representing thethermal energy being emitted from the area. The great amount,consistency and reproducibility of thermal energy in theconjunctiva/plasma interface and eyelid pocket allows obtaining a highsignal to noise ratio and accurate and precise determination of thesubstance of interest using far-infrared emission from the eye.

[1222]FIG. 104(Q5) shows a close-up view of the face and eyes with thesymmetric and great amount of infrared radiation being emitted by thecorner of both eyes which are seen as bright white spots. Note that theonly place in which bright spots can be seen is in the corner of the eyeindicating the highest amount of infrared energy being radiated. Thedarker the area the lesser amount of infrared energy being emitted. Thegreat amount, consistency and reproducibility of thermal energy in thecorner of the eye allows obtaining a high signal to noise ratio andaccurate and precise determination of the substance of interest usingfar-infrared emission from the corner of the eye. Illustrative resonanceabsorption peak for some exemplary substances of interest (wavelength innm) Albumin 2170 Bilirubin 460 Carbon dioxide 4200 Cholesterol 2300Creatinine 2260 Cytochromes 700 Ethanol 3300 Glucose 2120 Hemoglobin 600Ketones 2280 Lutetium texaphyrin 732 L-aspartyl chlorin e6 664 Oxygen770 Photoporphyrin 690 Porphyrins 350 Purlytin 664 Triglycerides 1715Urea 2190 Verteporfin 689 Water 11000

[1223] The body maintains ocular blood flow constant, whereas skin,muscle, and splancnic blood flow varies with changing cardiac output andambient conditions. Oxygen in the eye can continuously monitor perfusionand detect early hemodynamic changes. In addition, the oxygen levelsfound in the eyelid pocket reflects central oxygenation. The oxygenmonitoring in the eye can be representative of the general hemodynamicstate of the body. Many critical conditions such as sepsis (disseminatedinfection) or heart problems can alter perfusion in most of the body andit is thus difficult to evaluate adequacy of organ perfusion.

[1224] The eye though, remains with unaltered perfusion in such diseasestates and can provide a good indication of the level of oxygenation.FIG. 105(A) shows a simplified block diagram of ICL 2710 with oxygensensor 2712 and RF transceiver 2714 wirelessly connected to a pacemaker2716 and an internal cardiac defibrillator 2718. The contact device 2710for oxygen monitoring can be used for activating lifesaving equipmentsuch as pacemakers 2716, internal cardiac defibrillators 2718, and thelike. The defibrillator 2718 or pacemaker 2716 can be activated if thelevels of oxygen are within critical levels, for example during sleepingwhen the user is not capable to react to the life-threatening condition.The activation of the pacemaker 2716 or defibrillator 2718 is preferablydone when both the oxygen sensor 2710 and the heart tracing sensor 2720indicate a life-threatening condition. Other systems such as implantedconventional plethysmography can also work in association with the eyemonitoring systems to provide a more comprehensive monitoring.

[1225] The eye also provides a direct indication of heart beating andrhythm. FIG. 105(B) shows a tracing of heart beat achieved by using acontact device and transducer placed on the eye. The tracing gives awaveform corresponding to heart rhythm that can be used to monitorcardiac arrhythmia and cardiac contractility. The beating of the heartcan be detected and a change in heart rhythm used to activate orregulate lifesaving equipment.

[1226]FIG. 105(C) shows a block diagram in which the Intelligent ContactLens 2720 is used as heart monitor and coupled to an implanted pacemaker2716, an internal cardiac defibrillator 2718, an alarm system 2722, anda medication delivery system 2724 that can deliver for instance heartmedication to increase heart contractility or medication to correct anabnormal heart rate in order to meet oxygenation and perfusion needs ofthe patient.

[1227] The monitoring system can also be used as an intraoperativeawareness device. The phenomenon of intraoperative awareness occurs whena patient awakes during surgery and experiences pain. The anestheticwears off but because of muscle paralyzing drugs the patient, althoughawake, cannot react to the pain, speak, or move. However, the eyemuscles are activated when one awakens and the reverse Bell phenomenacan be used to gauge how awake the patient is. The reverse Bellphenomena relates to the eyes moving from a supero-temporal position toa straight gaze position when the individual awakens. The monitoringfunction can be accomplished by identifying the changes that occur withthe movement of the eye when the patient is awake. For instance, amotion or pressure sensor can be encased in the contact device andtransmit the information to an external receiver. In addition, thechange in rhythm as identified by the tracing in FIG. 105(B) can becombined with the above reverse Bell phenomena monitoring means and usedto gauge the degree of anesthesia.

[1228] With reference to FIGS. 105(D1-D7), a HTSD (Heat StimulationTransmission Device) is shown. Although the HSTD herein is described forthe eye, it is understood that the system can be used in the other partsand organs of the body. The HSTD 2711 is an arc shaped band with aradius of approximately 11.5 mm to fit in apposition to the sclera 2659.FIG. 105(D1) shows a cross-sectional view of the eye with the HSTD 2711implanted on the surface of the eye in apposition to the sclera 2659.The HSTD 2711 includes a heating element 2713, a temperature sensor 2715such as a thermocouple and a RF transceiver 2719 connected to thethermocouple 2715 by cable 2717. The heating element 2713 is locatedadjacent to the neovascular membrane 2729 being treated and located inthe most posterior part of the eye. The heating element 2713 emits heatranging from 40 to 41 degrees Celsius. This amount of heat deliveredover 12 hours restores function of abnormal vessels and closes leakingvessels with reabsorption of liquid leaking from the vessels. This HSTD2711 can be surgically implanted in the back of the eye in apposition tothe sclera 2659 or inside the sclera 2659, for treating cancer, maculardegeneration, diabetic retinopathy, neovascular membranes, veinocclusion, glaucoma, and any other vascular abnormalities present in theeye and the body. Besides surgical implantation, the HSTD can benoninvasively placed on the surface of the eye.

[1229] An LED, laser or other light sources delivering radiation in theinfrared region can also be used in the device 2711 as a substitute forheating element 2713. The use of the infrared wavelength including theuse of LEDs results in delivering radiation that is minimally absorbedby photoreceptors in the retina. The diameter of the LED, light sourceor heating element can preferably vary between 0.5 mm to 6 mm dependingon the size of the lesion being treated. A thermocouple 2715 can beincorporated to measure temperature real time which is transmitted to anexternal receiver 2725 via transceiver 2719.

[1230] The apparatus is based on the physiologic and anatomiccharacteristics of the eye. The eye has the largest supply of blood pergram of tissue and has the unique ability to be overperfused when thereis an increase in temperature. For each degree Celsius of increase intemperature there is an increase of about 7% in the oxygen levels in theeye. This increase in temperature causes dilation of the capillary bedand increased delivery of oxygen and can be used in situations in whichthere is hypoxia (decreased oxygenation) such as in diabetes, vascularocclusions, carotid artery disease, and the like. A higher increase intemperature and long term exposure causing localized hyperthermia leadsto vascular sclerosis and reabsorption of liquid and can be used in thetreatment of neovascular membranes as it occurs in age-related maculardegeneration. A further increase in temperature causes obliteration ofvessels and necrosis of rapidly duplicating cells and can be used fortreating tumors.

[1231] Besides surface electrodes, one exemplary and preferred way forgenerating heat for the HSTD is by using conductive polymers withself-regulating properties. Conductive polymers are made from a blend ofspecially formulated plastics and conductive particles. At predeterminedtemperatures the polymer assumes a crystalline structure through whichthe conductive particles form low-resistance chains in the polymermaterial that carry the current. With increased temperature thepolymer's structure changes to an amorphous state breaking theconductive chains and rapidly increasing the device's resistance. Whenthe temperature returns to its preset value the polymer returns to itscrystalline state and the conductive chains reform, returning theresistance to its normal value. At the preset temperature levels, notenough heat is generated to change the polymer to an amorphous state.When there is an excess heat the resistance rapidly increases with acorresponding decrease in the current and consequent decreased heatformation.

[1232] The apparatus of the present invention allows the tissue beingtreated to be maintained at a predetermined temperature. In additionminimum and maximum temperature can be set. The internal temperature andresistance depends on the chemical composition of that specific polymer.For any conductive polymer, there is a current that will raise thepolymer's internal temperature high enough to cause it to change from acrystalline to a non-crystalline or amorphous state. As current passesthrough the conductive polymer heat is generated. As the temperaturedrops, the number of electrical paths through the core increases andmore heat is produced. Conversely, as the temperature rises, the corehas fewer electrical paths and less heat is produced keeping thetemperature at a set predetermined level. The apparatus respondscontinuously to temperature increasing their heat output as thetemperature drops and decreasing heat output as the temperature rises.Such conductive polymers are available from the Raychem Corporation,Menlo Park, Calif.

[1233] The apparatus of the invention provides precisely the rightamount of heat at the predetermined location and time. The system designcan be adjusted to accommodate any type of disorder ranging from lowertemperature (less heat) for treating diabetic retinopathy to mediumrange temperature (38.5 to 40 degrees Celsius) to treat neovascularmembranes and higher temperature for treating cancer in the eye or anylocation in the body. The apparatus of the invention is low-cost andadjusts automatically to temperature changes. There is no need forspecial controls and no moving parts. Although the apparatus wasdescribed using polymers, ceramic, conductive paste, polymer thick filmsand a variety of polymeric positive temperature coefficient devices, andthe like can be used in the HSTD of the present invention. When usingsuch conductive polymers a lower cost system can be achieved. In thisembodiment the HSTD can include a power source and controller coupled tothe conductive polymer. There is no need for a temperature detector norRF transmitter.

[1234] Another preferred embodiment, besides heating, includes the useof a radioactive source. The radioactive source can also be used in thedevice 2711 as a substitute for heating element 2713. For example anactive seed such as Iodine-125 (I-125) or Paladium-103 (Pd-103) emittingx-rays and gamma rays can be used. A fiber-based delivery system fordelivering radiation which is encased in the HSTD 2711 can also be used.

[1235] Besides I-125 and Pd-103 other isotopes and Iridium can be used.Although, I-125 has a half-life of 59.61 days which would take about oneyear for complete inactivation, the device 2711 with the seed can beeasily removed at any time according to the response of the tissue.Exemplary seeds are available from North American Scientific, Inc.,Chatsworth, Calif.

[1236] The device 2711 with radioactive seeds can be used to treatneovascular membranes, vascular abnormalities, cancers, and the like andlength of implantation done according to the disease being treated. Fortreating neovascular membranes the device 2711 should be removed in lessthan 7 days with longer periods for treating cancer.

[1237]FIG. 105(D2) shows a side view of the arc-shaped HSTD 2711 withits elements 2713,2715, 2719 encased in it.

[1238]FIG. 105 (D3) shows a frontal view of the HSTD 2711 shaped as aband and with two small arms 2721 with holes 2721 a for fixating thedevice 2711 against the sclera 2659. Suture 2725 is passed through thehole 2721 a of arms 2721 to secure the device 2711 in a stable position.Multiple arms in different positions can be incorporated for fixatingthe device 2711 in a more stable position. The arc length of the device2711 is dependent upon the location of the lesion being treated.

[1239] FIGS. 105(D4-D6) show exemplary steps used for implantation. Thepatient looks down and a drop of anesthetic is placed on the eye. Thenan incision 2723 is made in the conjunctiva and device 2711 is slid overthe sclera 2659 toward the back of the eye. While the patient is stilllooking down, a couple of sutures 2725 are placed for fixation of device2711 to the sclera 2659 using the side arms 2721.

[1240]FIG. 105(D6) shows the device 2711 and microscopic sutures covetedby the conjunctiva 2320 and the upper eyelid 2411. After completion ofthe procedure the device 2711 is not visible and no discomfort elicited.After the lesion is treated the device 2711 can be easily removed withone drop of anesthetic with subsequent cutting the sutures 2725 andpulling the device 2711 out.

[1241]FIG. 105(D7) shows a frontal view of the HSTD 2711 shaped as across and with two holes 2721 a for fixating the device 2711 against thesclera 2659. This preferred HSTD is a low cost device only comprisingthe heating element 2713, cables 2717, and power source/controller 2717a. Multiple arms in different positions can be incorporated fordelivering a more widespread heat to the organ. The arms preferablyembrace the organ for achieving an intimate apposition. The arms areshaped according to the shape of the organ being treated.

[1242] Besides the sensor being encased in a conventional contact lensconfiguration as described above, the sensor part can be placed in theeye and subsequent to that a polymer that solidifies when in contactwith the eye is placed the eyelid pocket. This alternative embodimentcan be used for creating the housing for the sensor in-situ, meaning inthe eye pocket.

[1243] Additional Dispensing Capabilities:

[1244] Many patients go blind even after diagnosis and treatment for thedisease has been instituted. One classic example is glaucoma. Thetreatment of glaucoma requires the patient to instill eye drops on adaily basis in order to preserve their sight. Even after beingprescribed sight-saving eye drops, patients still go blind. Sometimespatients need to instill drops several times a day for a variety ofdiseases. Studies have shown that close to 60% of patients haddifficulties with self-administration of eye drops. Current means toadminister topical ocular drugs requires skills. The patient must notonly administer the drops with a correct amount, but also master arather difficult technique.

[1245] The technique recommended and most used for instilling eye dropswas described in the paper “How best to apply topical ocularmedication”. The process is not simple which explains the difficultiesrelated to using eye drops. The steps include: bending the neck, lookingup, looking away from the tip of the bottle to avoid fright reaction,pulling the lower eyelid down and away from the globe, positioning theinverted bottle over the eye but not touching any part of the eye,squeezing the bottle and placing the drop on the eye without touchingthe tip to the eye, to eyelids, or to eyelashes and yet without blinkingor lid squeezing when compressing the bottle. The problems described bypatients included: raising their arms above their heads, tilting theirheads, holding the bottle and squeezing the bottle with the arms raised,directing the bottle on top of the eye without touching the eye, fear ofhitting the eye leading the bottle to the held too high or away from theeye, involuntary blinking or closing eyes after squeezing the bottle,placing the correct number of eye drops, and poor view of the tip of thebottle.

[1246] With the dispensing ICL of the present invention, the user doesnot have to bend their neck in addition to not having to perform all ofthe other maneuvers described above. This ICL dispensing device andapplicator system of the present invention eliminates or substantiallyminimizes these difficulties and the consequent vision loss that occurdue to inability of instilling eye drops correctly.

[1247] The user can comfortably place the dispensing ICL on the eyeaccording to the following method and steps. The dispensing ICL isplaced on the eye under direct view and looking straight ahead. The userholds the handle in the ICL, place said dispensing ICL in the edge ofthe lower eyelid pocket while looking at a mirror. The remainder of thedispensing ICL then engages the surface of the cornea and the patientcloses his/her eye. The closure of the eye or blinking provides theactuating force to deform a reservoir and release the medication fromthe reservoir. The patient keeps the eye closed for 15 seconds to allowbetter absorption of the medication, then open the eyes, grasps thehandle and removes the dispensing ICL from the eye.

[1248] In FIG. 106(A), the Intelligent Contact Lens dispensing device2750 includes a self-contained substance source 2752 which is releasedby the physical displacement of a portion of the reservoir 2760 thereofwhereupon substance 2752 is forced to the outside and directed to thesurface of the eye. The substance 2752 self-contained in the reservoircan include liquid, gel, ointment, powder, pastes, gas, and the like.

[1249] Still with reference to FIG. 106(A), the apparatus include adispensing Intelligent Contact Lens 2750 adapted to facilitate thedispensing of substances 2752 such as eye drops, and preferably actuatedby eyelid motion. The apparatus is preferably utilized as a single useand is disposable. The Intelligent Contact Lens in FIG. 106(A) includesa main body 2754 to engage the surface of the eye and a reservoir 2760.The reservoir 2760 has the distal end 2756 partially covered with threemembranes 2758,2762,2764. The closure-seal membranes 2758,2762,2764 areapplied to the open distal end 2756 of the reservoir 2760 facing the eyesurface. Illustratively, the membrane 2764 spans a hole 2766 in the opendistal end 2756 of the reservoir 2760 to encapsulate the liquid orpowder inside said reservoir 2760. The membranes 2758, 2762, 2764 andwalls 2768 of the reservoir 2760 ensure leak-proof retention of thesubstance 2752 inside said reservoir 2760. The reservoir 2760 can bemade of elastic material which is compressible. The reservoir 2760component and surrounding main body structure 2754 is made to bedeformable by pressure applied against said reservoir.

[1250]FIG. 106(B) shows the main body 2754 joined by a shaft 2772 whichis connected to a handle 2774. The handle 2774 is used to facilitateplacement and removal of the dispensing ICL 2750 to and from the eye.

[1251] In reference to FIG. 107(A), the actuating element to causedeformation of the reservoir 2760 with extrusion of its contents ispreferably provided by pressure applied by the eyelid 2770 duringblinking or closure of the eye. The eyelid motion provides the mostuniversal and natural actuating force. Everybody without disease blinksin the same manner. People from difference races blink in the samemanner. The process of blinking in a normal person does not age and a 70year old person blinks in the same manner as a 20 year old. The closureof the eye or blinking produces a 10 mmHg increase in pressure andapplies a force of 25,000 dynes against the exterior surface of the mainbody 2754 and reservoir 2760.

[1252]FIG. 107(A) also shows this squeezing pressure by the eyelid 2770which exceeds the bursting strength of the membrane portion 2764 and themembrane 2764 is then ruptured. FIG. 107(A) yet shows the dispensing ICL2750 partially compressed in its upper part encompassing membrane 2764by the squeezing pressure of the eyelid 2770. The liquid 2752 isexpelled from reservoir 2760 and directed toward the surface of the eyeand absorbed by the eye. The liquid permeates the cornea 2776 and can beseen in the anterior chamber 2778 of the eye.

[1253]FIG. 107(B) shows the dispensing ICL 2750 completely compressed bythe eyelid 2770 with the medication 2752 absorbed by the eye and presentin large quantities in the anterior chamber 2778 of the eye. The mainbody 2754 of the compressed dispensing ICL 2750 serves as a surface toincrease retention time.

[1254] Another advantage of the present dispensing means is the abilityof increasing retention time by interposing a surface such as the mainbody 2754 against the fluid 2752 which increases penetration. Oneimportant problem when administering topical eye drops is that themedication is drained through the lacrimal canal and absorbed by thecirculation in the nose and throat. This is experienced when applyingeye drops, when one can taste the drops. A serious problem, includingdeath reported in the literature, occur due to the absorption of eyedrops by the naso-pharingeal circulation.

[1255] By increasing retention time as provided with the methods andapparatus described herein, there is elimination or reduction ofunwanted drainage and systemic absorption of medications designed to beused in the eye. The increased retention time and surface barrier by themain body 2754 of the dispensing ICL 2750 prevents the unwanted drainageof the eye medication. Thus, the dispensing ICL provides a much saferway for the delivery of medications to the eye. In addition, the ICLdispensing system 2750 provides a more cost-effective solution. Theincreased retention time increases absorption of medication by the eye,and thus less medication is wasted.

[1256] Although, the preferred embodiment includes a reservoir withmembranes that can be broken, it is understood that the dispensingfunction can be accomplished without the rupture of the membrane. Thepressure applied by the eyelid during closure of the eye can causeincreased permeation of the wall and membranes to the medication presentinside the reservoir. The medication can then reach the eye surfacethrough intact walls of the reservoir and without fracture of the sealto initiate passage of the liquid. Although the cornea was described asa preferred embodiment, other parts in the surface of the eye can beused for placement of the dispensing ICL with the actuation meanspreferably provided by the squeezing pressure of the eyelid. Although apermanently fixed shaft 2772 and handle 2774 was described, it isunderstood that a detachable shaft 2772 and handle 2774 can be used.

[1257] It is also understood that although reservoirs were used, asponge-like material that absorbs fluid a certain predetermined amountover a set period of time can be used. The sponge dispensing ICL is thenplaced on the eye in a similar fashion. The pressure of the eyelidduring closure of the eye can then squeeze the fluid present in thesponge structure. Multiple membranes can also be used to allow themedication to be in contact with a large surface of the eye for betterabsorption as well as a combination of multiple membranes and a spongepart.

[1258] Although the preferred embodiment relates to using blinking asthe actuating force, it is understood that squeezing of the eyelids orapplying pressure from the outside can be used as actuating means. FIG.108 shows pressure being applied by an external source 2880 such as afinger or massage motion against the closed eyelids 2770 with thedispensing ICL 2750 underneath said eyelid 2770. This alternativeembodiment can be used by patients with severe disorders of the musclesof the eyelid or with eyelid nerve damage as means to enhance pressureapplied by said diseased eyelid. Pressing with the finger or massagingthe dispensing ICL is less desirable due to the enormous variation inforce applied and risk of injury.

[1259] Although, the preferred embodiment uses a membrane that can befractured under pressure, it is understood that a one way valve, singleor multiple, alone or in combination with fracturable membranes can beused. Any other means, valves, or membranes that retain the substance inthe reservoir and which release the substance upon deformation can beused in the dispensing ICL.

[1260]FIG. 109 shows a dispensing ICL 2750 with a dual reservoir 2882,2884, for example, with two different medications including timolol gel2886 and latanoprost 2888 which are medications used for glaucomatreatment. A single or multiple reservoir configuration can be used forsingle or multiple delivery of medications.

[1261] In order to facilitate placement, handles can be included andgrasped by fingers or forceps for insertion without touching the mainbody. Alternatively the body can be made out of magnetic material and amagnetic applicator used for placement and removal of the dispensingICL. In addition, part of the main body can be made of rigid material toallow securely grasping of the dispensing ICL without touching thereservoirs.

[1262] An alternating embodiment for the dispensing ICL is shown inFIGS. 110(A) and 110(B). This alternative embodiment isolates the liquidfrom the main body of the contact device engaging the eye. The apparatusincludes a liquid containing squeezable bulb 2890 joined by a conduit2892 to a main body contact device 2900 in apposition to the eye 2894. Arupturable membrane or seal 2896 contains and isolates the liquid 2752from the main body contact device 2900 and keep said liquid 2752confined to the storage bulb 2890. The contact device 2900 is connectedby a conduit 2892 to the storage bulb 2890. The contact device 2900 hasmultiple openings 2902 in its concave surface through which the liquid2752 from the conduit 2892 flows to the surface of the eye 2894. Thecontact device 2900 serves to direct the liquid 2752 to the surface ofthe eye 2894 and to increase retention time for the liquid 2752 beingapplied to the eye 2894.

[1263] In use the patient places the contact device 2900 on the surfaceof the eye 2894 and squeezes the bulb 2890. FIG. 110(B) shows the bulb2890 partially squeezed by pressure P to illustrate the dynamics of thedispensing process. This pressure P directs the liquid 2752 against theseal 2896 to cause its rupture and force the liquid 2752 through theconduit 2892. The liquid 2752 then travels to the contact device 2900,enters the channel 2904 and is delivered to the surface of the eye 2894,which includes the cornea and/or conjunctiva. The dimensions of bulb2890 and contact device 2900 are made to deliver the appropriate amountof medication according to the prescribed dosage by the doctor.

[1264] Although one storage area in the bulb was described, it isunderstood that multiple storage areas in the bulb can be used. Besides,the storage bulb can be of a detachable type. The storage bulb can havetwo compartments, one with air and one with liquid and a dual membraneseal. The first membrane seal is interposed between the air and liquidstorage areas and the second membrane seal between the liquid storagearea and the conduit. This embodiment allows delivery of the totalamount of liquid in the storage liquid compartment as the air fills theremainder of the conduit and contact device. In addition, tubular meansconnected to the storage bulb or a medication dispenser can be used tocreate a gap in the eyelid pocket and precisely deliver the medicationinto said eyelid pocket. This can be done with the tubular fluiddelivery means alone or coupled to a member that facilitate positioningand/or opening of the eyelid pocket.

[1265] The reservoir with the medication can be encased in the main bodyduring manufacturing or assembly of the ICL by conventional contact lensmanufacturing means. A variety of conventional manufacturing processesfor contact lens can be used including injection molding, light-curedpolymerization, casting process, sheet forming, compression, automaticor manual lathe cutting techniques, and the like. An exemplary way caninclude placement in the molding cavity of a pellet which has themedication sealed with a membrane. The polymer injected in the cavitysurrounding the pellet forms the body of the dispensing ICL. The pelletcontaining medication encased by the surrounding polymer turns into thereservoir in the dispensing ICL.

[1266] While several embodiments of the present invention have beenshown and described, alternate embodiments and combination ofembodiments and/or features will be apparent to those skilled in the artand are within the intended scope of the present invention.

I claim:
 1. A contact device for placement adjacent to the conjunctivaof the eye, said contact device comprising: a housing for placementadjacent to the conjunctiva of the eye, a sensor contained in thehousing for analyzing fluid from the conjunctiva for at least one ofchemical, physical, cellular and molecular evaluation, and said housingbeing less than 5.0 mm in thickness.
 2. An apparatus for noninvasivemeasurement of the concentration of at least one substance in the eye,said application comprising: a source of electromagnetic radiation forirradiating the eye, and a detecting device for detecting an intensityof electromagnetic radiation emitted by the substance being measured andproviding an output signal representative of the detected intensity ofsaid radiation.
 3. The apparatus of claim 2, wherein the detectingdevice, the source of radiation and a collector of radiation are locatedside-by-side in a housing.
 4. The apparatus of claim 2, wherein thedetecting device, the source of radiation and a collector of radiationare located opposed to each other in a housing.
 5. The apparatus ofclaim 2, further comprising a filter for selecting a wavelengthcorresponding to infrared energy absorbed by the substance beingmeasured.
 6. The apparatus of claim 2, further comprising a contactdevice for placement on the eye.
 7. The apparatus of claim 6, furthercomprising a housing for placement of the contact device inside the eye.8. The apparatus of claim 6, wherein the contact device is anintraocular lens.
 9. The apparatus of claim 2, wherein said at least onesubstance includes at least one of glucose, cholesterol and ethanol. 10.The apparatus of claim 3, further comprising a filter for selecting awavelength corresponding to absorption of infrared energy by thesubstance being measured.
 11. The apparatus of claim 10, wherein thefilter has a bandwidth centered on about 2,120 nm.
 12. The apparatus ofclaim 10, wherein the filter has a bandwidth centered on about 2,300 nm.13. The apparatus of claim 10, wherein the filter has a bandwidthcentered on about 3,300 nm.
 14. The apparatus of claim 2, furthercomprising a wireless device for transmitting the output signal to aprocessor.
 15. The apparatus of claim 3, wherein the housing has a penconfiguration.
 16. The apparatus of claim 4, wherein the housing has aforceps configuration.
 17. The apparatus of claim 2, further comprisinga drug delivery device actuated by said output signal.
 18. The apparatusof claim 2, wherein the detector is an infrared sensor.
 19. Theapparatus of claim 2, further comprising a cardiac defibrillatoractivated by said output signal.
 20. The apparatus of claim 2, furthercomprising a pacemaker activated by said output signal.
 21. A method fornoninvasive measurement of at least one substance in the eye, saidmethod comprising the steps of: irradiating the eye with electromagneticradiation, and detecting an intensity of electromagnetic radiationemitted by the substance being measured and providing an output signalrepresentative of the intensity of said radiation.
 22. An apparatus fornoninvasive measurement of a concentration of at least one substance inthe eye, said application comprising: a detecting device for receivinginfrared energy from the eye and for measuring infrared absorption of atleast one substance present in said eye based upon the infrared energygenerated by the eye, and a processing device for determining theconcentration of the at least one substance based upon the infraredabsorption.
 23. The apparatus of claim 22, wherein said at least onesubstance includes at least one of glucose, ethanol and cholesterol. 24.The apparatus of claim 22, further comprising two narrow band passfilters disposed between the eye and said detecting device, one of thenarrow bandpass filters passing infrared energy in a wavelengthcorresponding to absorption of said infrared energy by the substancebeing measured and the other of the narrow bandpass filters passinginfrared energy outside the wavelength of absorption of the substancebeing measured.
 25. The apparatus of claim 24, wherein said one filterhas a bandwidth centered on about 9,400 nm and the other filter has aband width centered at between 10,500 and 11,000 nm.
 26. The apparatusof claim 24, wherein said one filter has a bandwidth centered on about9,900 nm and the other filter has a band width centered at between10,500 and 11,000 nm.
 27. The apparatus of claim 24, wherein said onefilter has a bandwidth centered on about 8,300 nm and the other filterhas a band width centered at between 10,500 and 11,000 nm.
 28. Theapparatus of claim 21, wherein a cooling device is used to increase atemperature gradient between a cold junction and a hot junction of aninfrared sensor of said detecting device.
 29. An apparatus fornoninvasive measurement of a concentration of at least one substance inthe eye, said application comprising: a detecting device for detectingradiation intensity of two wavelengths of light in an infrared regionemitted by said eye with said detecting device detecting radiationintensity of the two wavelengths with one of said wavelengths having ahigh absorption correlation with the substance being measured and theother of said wavelengths having a lower absorption correlation with thesubstance being measured and providing an output signal, and aprocessing device for processing the output signal obtained from thedetecting device for determining the concentration of the at least onesubstance according to the absorption of infrared energy by saidsubstance.
 30. A method for noninvasive measuring at least one substancein the eye, said method comprising the steps of: receiving and detectinginfrared energy from said eye, determining infrared absorption of atleast one substance present in said eye from said infrared energy fromsaid eye, and processing and determining the concentration of said atleast one substance from the infrared absorption.
 31. A method fornoninvasive measurement of at least one substance in the eye, saidmethod comprising the steps of: detecting two wavelengths in theinfrared region emitted by said eye with one of said wavelengths havinga high absorption correlation with the substance being measured and theother of said wavelengths having a lower absorption correlation with thesubstance being measured, and processing the detected wavelengths fordetermining a concentration of at least one substance according to theabsorption of infrared energy by said substance.
 32. An apparatus fornoninvasive measurement of at least one substance in the eye, saidapparatus comprising: a receiving device for receiving infrared energyfrom said eye, a detecting device for determining infrared absorption ofat least one substance present in said eye from the infrared energygenerated by said eye, a sensor for measuring temperature of said eye, aprocessing device for determining temperature of the eye and theconcentration of at least one substance based upon the infraredabsorption and the measured temperature.
 33. A method for noninvasivemeasurement of at least one substance in the eye, said method comprisingthe steps of: receiving infrared energy from said eye, determining anamount of infrared absorption of at least one substance present in saideye from the infrared energy generated by said eye, measuringtemperature of said eye, and determining the amount of the concentrationof at least one substance based upon the infrared absorption andtemperature of the eye.
 34. An apparatus for measuring temperature, saidapparatus comprising: a contact device to engage a surface of the eye,said contact device including a device for detecting temperature on thesurface of said eye and for transmitting a detection signalrepresentative of the temperature exteriorly of the contact device. 35.The apparatus of claim 34, wherein the device includes a wirelesstransmission device.
 36. The apparatus of claim 34, further comprising adevice for activating another device based-upon a temperature level. 37.The apparatus of claim 36, wherein said device includes a detector fordetecting infectious agents.
 38. Method for measuring temperature on theeye, said method comprising the steps of: placing a contact device on asurface of the eye, detecting a temperature on the surface of said eye,and transmitting a detection signal representative of the detectedtemperature and a temperature level according to the detection signalacquired at the transmitting step.
 39. An apparatus for noninvasivemeasurement of the concentration of at least one photosensitizing drugin the eye, said application comprising: a source of electromagneticradiation for irradiating the eye, a detecting device for detecting anintensity of electromagnetic radiation emitted by the eye afterelectromagnetic radiation from the source interacts with thephotosensitizing drug being measured and providing an output signalrepresentative of the intensity of said radiation, and a processingdevice for calculating the concentration of said photosensitizing drugfrom said detected electromagnetic radiation intensity.
 40. Theapparatus of claim 39, wherein the electromagnetic radiation irradiatingthe eye has a shorter wavelength than the absorption wavelength of saidphotosensitizing agent.
 41. The apparatus of claim 39, wherein theelectromagnetic radiation irradiating the eye is centered at 690 nm. 42.The apparatus of claim 41, wherein the detecting device detects anintensity of fluorescence generated by said electromagnetic radiation.43. The apparatus of claim 39, wherein said photosensitizing drugincludes at least one of verteporfin, purlytin, and lutetium texaphyrin.44. The apparatus of claim 39, further comprising a radiation deliverydevice to treat an abnormal condition according to a concentration ofthe photosensitizing drug.
 45. A method for treating abnormal conditionsof a body organ, said method comprising the steps of: placing a contactdevice in apposition to tissue of the body organ, using said contactdevice for delivering radiation to said tissue, and permittingsufficient time to elapse to allow delivery of radiation to said tissueso as to treat said abnormal condition.
 46. The method of claim 45,wherein the radiation includes at least one of infrared, x-rays andgamma rays.
 47. The method of claim. 46, wherein the infrared radiationincludes heat generated by a conductive polymer.
 48. The method of claim46, wherein the x-rays and gamma rays include radiation delivered usingradioactive seeds.
 49. The method of claim 45, wherein said abnormalconditions include at least one of hypoxia, abnormal vasculature,glaucoma and cancer.
 50. The method of claim 45, wherein the radiationsource delivers at least one of infrared, x-rays and gamma rays.
 51. Anapparatus for treating abnormal conditions of the eye comprising: acontact device for contacting tissue of said eye, and a radiation sourcefor delivering radiation to said tissue of said eye so as to treat saidabnormal condition.
 52. The apparatus of claim 51, further comprising atemperature detector.
 53. The apparatus of claim 51, wherein infraredradiation is delivered by a conductive polymer.
 54. The apparatus ofclaim 51, wherein the x-rays and gamma rays are delivered by radioactiveseeds.
 55. The apparatus of claim 51, wherein said abnormal conditionsinclude at least one of hypoxia, abnormal vasculature, glaucoma andcancer.
 56. A dispenser for applying medication to an eye, saiddispenser comprising: a contact device for engaging the surface of theeye, at least one bulb containing medication to be dispensed, said bulbbeing compressable by external pressure causing expulsion of medicationto a surface of the eye.
 57. The dispenser of claim 56, wherein saidbulb has rupturable membranes.
 58. A dispenser for applying medicationto an eye, said dispenser comprising: a contact device for engaging thesurface of the eye, said device containing a canal connected to a shaft,said shaft being connected to a squeezable bulb, said squeezable bulbcontaining medication with said medication being expelled to a surfaceof the eye upon squeezing said bulb.